Use of cgrp receptor antagonists in neuroprotection and neurological disorders

ABSTRACT

Provided herein are treatment methods, including methods of treating nerve damage, methods of neuroprotection, methods of treating glaucoma and methods of lowering LDL levels. The methods generally involve administering to an individual in need thereof an effective amount of a CGRP receptor antagonist peptide or composition.

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

This application is a Continuation of and claims the benefit of priorityto U.S. patent application Ser. No. 16/329,596, filed on Feb. 28, 2019,which is a U.S. National Phase Application of PCT InternationalApplication Number PCT/US2017/049460 filed on Aug. 30, 2017, designatingthe United States of America and published in the English language,which claims the benefit of priority to U.S. Provisional Application No.62/383,334, filed on Sep. 2, 2016, all of which are hereby expresslyincorporated by reference in their entireties.

REFERENCE TO SEQUENCE LISTING, TABLE, OR COMPUTER PROGRAM LISTING

The present application is being filed along with a Sequence Listing inelectronic format. The Sequence Listing is provided as a file entitledCSOAR-003D1.TXT, created Jun. 9, 2022, which is 17 kb in size. Theinformation is the electronic format of the Sequence Listing and isexpressly incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present embodiments relate to the therapeutic use of antagonists ofthe calcitonin gene-related peptide (CGRP) receptor for neuroprotectionand in the treatment of acute and chronic diseases and disordersassociated with neurodegeneration, including for example, treatment ofglaucoma. In addition, methods of treating diseases related to high LDLlevels, using the antagonists, are provided herein.

BACKGROUND

Calcitonin gene-related peptide (CGRP), a member of the calcitoninfamily of peptides, is a potent 37-amino acid peptide vasodilator thathas an important role in the pathogenesis of several pain syndromes,such as migraine, and thermal injury. In addition to its role invasodilation, CGRP can exert a broad range of biological effects.

CGRP (calcitonin gene-related peptide) is a well-studied peptide in thecalcitonin/calcitonin gene-related peptide (CT/CGRP) family of peptidehormones, which can act as a sensory neuropeptide with potentvasodilatory and cardiotonic action as described in U.S. Pat. No.4,530,838 to Evans, et al. CGRP is present in both the central andperipheral nervous systems and is concentrated in those areas of thebody receiving sensory input from the dorsal horn with limited amountsassociated with autonomic input. In the brain, the peptide is present inthe nuclei of sensory and motor cranial nerves and in cell bodies in thehypothalamus, preoptic area, ventromedial thalamus, hippocampus, and thelike (Poyner et al. 1992).

The CT/CGRP peptide family includes calcitonin gene-related peptide(CGRP), adrenomedullin (ADM), intermedin (IM), calcitonin (CT) andamylin. The biological actions of these peptides are mediated viabinding to two closely related type II G protein-coupled receptors(GPCRs), the calcitonin receptor (CTR) and the calcitonin receptor-likereceptor (CRLR) (Christopoulos, et al. 1999; Poyner et al. 2002). Thecalcitonin receptor is the main mediator for calcitonin action. However,it preferentially binds amylin, when the receptor is associated with areceptor activity modifying protein (RAMP) (see, e.g., Tilikaratne, etal. 2000). Cloning and functional studies have shown that CGRP, ADM, IMand, to a lesser extent, amylin likewise interact with differentcombinations of CRLR and the three receptor activity modifying proteins(RAMP-1, RAMP-2 and RAMP-3) (see, e.g., McLatchie et al. 1998, and Rohet al. 2004). Co-expression of the calcitonin receptor-like receptor(CRLR) and receptor activity-modifying proteins (RAMPs) is required togenerate functional heterodimer receptors for calcitonin gene-relatedpeptide (CGRP), adrenomedullin (ADM) and intermedin (IM). Co-expressionof RAMP-1 with CRLR leads to the formation of a CGRP receptor, whereasRAMP-2 and RAMP-3 co-expression with CRLR form ADM and IM receptors,respectively (Miret, et al. 2002). IM has been shown to be anonselective agonist for all three RAMP/CRLR co-receptors.

CGRP initiates biological responses by binding to the CGRP receptor. TheCGRP receptors are composed of 3 subunits: a 7 transmembrane proteincalled the calcitonin-like receptor (CLR), a single transmembraneprotein that determines ligand specificity called receptor activitymodifying protein 1 (RAMP1) and an intracellular protein called receptorcomponent protein (RCP). The CGRP receptor is coupled to the Gassignaling pathway leading to increased intracellular cAMP and activatedprotein kinase A (PKA) (Poyner et al., 2002).

CGRP receptors are found in multiple areas, including for example: 1)the cerebrovasculature smooth muscle, where they can cause relaxation ofthe vessels (Poyner et al., 2002); 2) dural mast cells from which CGRPhas been shown to release pro-inflammatory cytokines and inflammatoryagents during neurogenic inflammation (Marquest et al., 2006); 3)trigeminal ganglia neurons (Zhang et al., 2007) and second order sensoryneurons within trigeminal nuclei in the caudal brainstem which isresponsible for the transfer of pain sensation (Russo et al., 2015).

CGRP receptors are expressed in the central and peripheral nervoussystem (Cumberbatch et al., 1999; Marquez de Prado et al., 2006).Inhibitors at the receptor level to CGRP are postulated to be useful inpathophysiologic conditions where excessive CGRP receptor activation hasoccurred. Some of these include neurogenic vasodilation, neurogenicinflammation, migraine, cluster headache and other headaches, thermalinjury, circulatory shock, menopausal flushing, and asthma. CGRPreceptor activation has particularly been implicated in the pathogenesisof migraine headache (Edvinsson et al. 2001; Grant et al., 2002).Migraines are noted for the strength of the headache that ensues withits pathology. It is postulated that the headache associated withmigraines results from the profound cerebral vasodilation associatedwith migraine events. CGRP-containing nerve fibers innervate cerebraland dural vessels where CGRP is believed to prolong vasodilation.(Moskowitz et al. 1992). Further, serum levels of CGRP are elevatedduring migraine (Goadsby, et al. 1990), and treatment with anti-migrainedrugs returns CGRP levels to normal coincident with alleviation ofheadache (Gallai, et al. 1995). Migraineurs exhibit elevated basal CGRPlevels compared to controls (Ashina, et al., 2000). Intravenous CGRPinfusion produces lasting headache in migraineurs (Lassen, et al. 2002).CGRP antagonist peptides and their use in the treatments of migraineshave been described in U.S. patent application Ser. No. 13/821,936 filedon Mar. 8, 2013 (Soares et al.), hereby incorporated by reference in itsentirety.

Nerve injury can also lead to high levels of CGRP in the nerves andspinal cord. In a study performed by MDBiosciences, levels of CGRP mRNAwere markedly increased in pigs that sustained neuritis neuropathy dueto sciatic nerve injury (Castel et al. 2016).

Antagonists of the CGRP receptor are known, including small molecule,peptide and antibody antagonists. Small molecule antagonists of the CGRPreceptor include, for example, the gepant class of molecules, such asolcegepant, telcagepant and ubrogepant. Peptide antagonists include, forexample, truncated CGRP peptides such as CGRP (8-37), CGRP (28-37),[Tyr^(o)]CGRP (28-37), and CGRP (12-37); h-α-CGRP (9-37), h-α-CGRP(10-37), h-α-CGRP (11-37) (Mimeault, M. et al., 1992); [Ala⁹]-h-α-CGRP(8-37), [Ala¹⁰]-h-α-CGRP (8-37), [Ala¹¹]-h-α-CGRP (8-37), and[Ala¹²]-h-α-CGRP (8-37), id; and h-α-CGRP (19-37), h-α-CGRP (23-37) andacetyl-h-α-CGRP (19-37) (Rovero, P. et al. 1992).

Non-truncated peptide antagonists of CGRP receptors are described, forexample, herein and in Soares, C J, PCT Patent Publication WO2013/112912, published Aug. 1, 2013. Such non-truncated, or full lengthpeptide antagonists of CGRP receptors have been shown to be highlypotent antagonists that would not be expected to have off-targeteffects, as seen with many small molecule antagonists. Additionally,antibodies binding CGRP receptors are known, such as AMG 334, as areantibodies to the CGRP ligand, such as LY2951742, ALD403 and TEV-48125.To date, such CGRP receptor and ligand antibodies have been investigatedfor use in treatment of pain-related disorders such as migraine andosteoarthritis pain.

Every year, millions of people worldwide suffer the consequences ofneurodegeneration caused by injury or disease. The umbrella term,neurodegenerative disease, refers to the progressive loss of structureand/or function of the neurons including the death of neurons. Examplesof neurodegenerative disease include glaucoma, amyotrophic lateralsclerosis, multiple sclerosis, Creutzfeld-Jakob disease, epilepsy,Parkinson's, Alzheimer's, diabetic neuropathy and Huntington's disease(Gupta, et al., 2007; Song et al., 2016; Mufson et al). To date, nocures exist for such diseases which typically result in progressivedegeneration and/or the death of neuron cells and can result in death ofthe patient. Neurodegeneration can be found in many different levels ofneuronal circuitry ranging from molecular to systemic.

Glaucoma is a neurodegenerative disease that is one of the most commoncauses of blindness, affecting over 70 million people worldwide. Anage-related, chronic degenerative disease of the optic nerve, retina,and brain, glaucoma exhibits similarities to the molecular and cellularfeatures of other chronic degenerations of the neurologic systems,including amyotrophic lateral sclerosis. The underlying mechanismsleading to glaucoma are still under investigation, however onewell-established cause of glaucoma is the damage to retinal ganglioncells from the result of mechanical injury stemming from intraocularpressure caused by disruption of the trabecular meshwork (Nafissi et al.2015). Glaucoma comprises a group of several eye diseases that lead todamage to the optic nerve and, too often, vision loss. While glaucoma isgenerally characterized by the increase of intraocular pressure (IOP),damage to the ganglion cells of the retina and the optic nerve withoutconcomitant increase in IOP is also a known form of glaucoma(normotensive glaucoma). Similarly, genetic mutation and oxidativeinsult can lead to ganglion cell apoptosis. As such, there is a need todevelop strategies for protecting the ganglion cells of the retina andthe optic nerve.

In a recent review of glaucoma, it was suggested that axonopathy, adisorder affecting primarily the normal functioning of axons ofperipheral nerve fibers in the brain can also lead to glaucoma (Chaderet al., 2012). The changes in the optic nerve and the optic nerve headcan include impairment of transport of molecules in the fibers of theoptic nerve that causes glaucomatous damage to accumulate as the patientgets older. Injury of specialized brain structures is also seen in theearly stages of glaucoma. Glaucoma can also stem from a complicationfrom diabetic eye disease. People with diabetes are twice as likely todevelop glaucoma compared to non-diabetics as they age.

Thus, neurodegeneration is a complex disease, in which several groups ofpeople are at a substantially higher risk than the general populationfor developing diseases that affect the nerve fibers. One of thegreatest risk factor for neurodegenerative diseases is aging. Forexample, mitochondrial DNA mutations as well as oxidative stress areassociated both with aging and other neurodegeneration.

Aging is another factor that can lead to glaucoma. For example, agingcan play a role in the development of primary open-angle glaucoma(POAG). As such, advances in other age-related diseases may be useful inthe development of a variety of treatments. For example, methods thatare developed to protect the neurons of the optic tract may also beapplied to other nervous system diseases, such as Alzheimer's diseaseand AMD, for example, where neurons are in need of protection.

Thus far, treatments for have focused on lowering intraocular pressure,such as the FDA-approved prostaglandins (i.e. Xalatan, Lumigan, TravatanZ and Rescula), beta-blockers (i.e. Timoptic XE, Istalol and Betopic)and alpha adrenergic agonists (i.e. iopidine, Alphagan and Alphagan-P).Some of these drugs were first used for other purposes but weresubsequently found to be safe and efficacious in treating glaucoma. Asthese drugs are drops applied to the surface of the eye, they arerelatively low risk. However, these drugs are not effective in all casesof glaucoma and do not constitute a cure, but they can be used toprolong functional vision in treated patients. Thus there remains a needfor therapies that achieve better management of the disease, furtherreducing or preventing vision loss.

Methods to protect neurons can lead to inhibiting the onset ofneurodegenerative diseases and inhibiting damage of neurons, includingretinal neurons, such as photoreceptor cells against cell death(apoptosis) or can lead to slowing of neurodegenerative diseaseprogression and associated damage to neurons. Thus these new methods canbe used to prevent and/or slow nerve injury or protect retinal neuronsor nerves in the peripheral or central nervous system.

SUMMARY

The present disclosure is based on the discovery that CGRP receptorantagonists, including, for example, peptide antagonists, can be used toinhibit or decrease neuronal damage including neuronal death and provideneuroprotection. CGRP receptor antagonists and compositions comprisingthe same can be used to treat neurodegenerative diseases. Without beinglimiting, these CGRP antagonist peptides and compositions can be used toprotect neurons from acute or chronic damage, inhibiting or slowing celldeath and thereby treating disorders associated with neuronal damagesuch as, for example, glaucoma, neuropathy, spontaneous nerve activityand neuritis.

Also disclosed is the use of CGRP receptor antagonists to reduce levelsof LDL, thereby treating diseases resulting from high LDL levels.

In a first aspect, a method of reducing spontaneous activity of nervesin a patient, in need thereof is provided. The method comprisesadministering to the patient an effective amount of CGRP receptorantagonist including a pharmaceutically acceptable salt thereof. In someembodiments, the CGRP receptor antagonist is a peptide comprising astructure of Formula I.

X¹—Y¹—Z¹   (I)

wherein X¹ is a modified N-terminal fragment (i.e., region) ofcalcitonin gene-related peptide comprising from five to seven amino acidresidues, wherein only two amino acid residues of the N-terminalfragment are cysteine (Cys), wherein the residue at the C-terminal endof the region is Cys, and wherein the residue immediately preceding theC-terminal Cys residue of the region is a non-threonine substitution ofthe threonine (Thr) residue of position 6 of human CGRP, Y¹ is a centralcore region wherein at least one amino acid of the central core isarginine (Arg) or lysine (Lys) and the central core comprises anα-helix, and Z¹ is a modified C-terminal fragment (i.e., region) ofcalcitonin gene-related peptide comprising from five to seven amino acidresidues with a C-terminal amide, where at least one amino acid of theC-terminal fragment is phenylalanine (Phe), tyrosine (Tyr), proline(Pro) or hydroxyproline (Hyp). In some embodiments, the CGRP receptorantagonist is a peptide comprising a sequence set forth in one of SEQ IDNO: 1(NH2-Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 2(NH2-Ala-Cys-Asp-Thr-Ala-Ser-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 3(NH2-Ala-Cys-Asp-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 4(NH2-Ala-Cys-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 5(NH2-Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 6(NH2-Ala-Cys-Arg-Phe-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 7(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 8(NH2-Cys-Ser-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 9(NH2-Ala-Cys-Asp-Thr-Ala-Leu-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 10(NH2-Ala-Cys-Asp-Thr-Ala-Ile-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 11(NH2-Ala-Cys-Asn-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 12(NH2-Cys-Ser-Asn-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 13(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2),SEQ ID NO: 14(Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Val-Asp-Pro-Ser-Ser-Pro-His-Ser-Tyr-NH2),SEQ ID NO: 15(Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Thr-His-Arg-Leu-Ala-Gly-Leu-Leu-Ser-Arg-Ser-Gly-Gly-Val-Val-Lys-Asn-Asn-Phe-Val-Pro-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 57(NH2-Ala-Cys-Asp-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or SEQ ID NO: 58(NH2-Ala-Cys-Asp-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or a pharmaceutically acceptable salt thereof. In some embodiments, theCGRP receptor antagonist comprises a sequence selected from the groupconsisting of the sequences set forth in SEQ ID NO: 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12 and 13. In some embodiments, the CGRP receptorantagonist is administered topically, dermally, intradermally,subcutaneously, via dermal infusion, via subcutaneous infusion,intraocularly, buccally, intravenously, nasally, via inhalation,intramuscularly, sublingually or orally. In some embodiments, theeffective amount comprises an amount of about 50 μg, 60 μg, 70 μg, 80μg, 90 μg, 100 μg, 200 μg, 300 μg, 400 μg, 500 μg, 600 μg, 700 μg, 800μg, 900 μg, 1 mg, 5 mg, 10 mg, 40 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg or any amount inbetween a range defined by any two aforementioned values. In someembodiments, the administering is performed at least once daily, once aweek, twice a week or three times a week, or four times a week. In someembodiments, the spontaneous nerve activity is due to a nerve injury orneurodegenerative disease. In some embodiments, the nerve injury is froma physical injury, diabetes, cancer, diabetic neuropathy, head injury,seizures, infection, or ingestion of a pharmaceutical or drug, such as achemotherapeutic. In some embodiments, the neurodegenerative disease isamyotrophic lateral sclerosis, multiple sclerosis, Creutzfeld-Jakobdisease, epilepsy, Parkinson's, Alzheimer's, glaucoma, cerebrovascularischemia, motor neuron disease, dementia, diabetic neuropathy orHuntington's disease. In some embodiments, the patient has beenidentified or selected to receive a drug for neurodegenerative diseases,neurovascular disorder or disease such as cancer. In some embodiments,the drug is associated with spontaneous nerve activity and/or nervedamage. In some embodiments, wherein the nerve injury is from apharmaceutical or drug, the pharmaceutical or drug is a heart medication(i.e. almitrine), an anti-cancer drug, antibiotic (i.e. chlorampheticol,Cipro), anti-fungal, immunosuppressant drug (i.e. Cyclosporine), musclerelaxant (i.e. Hydrazaline), anti-seizure medications (i.e. Phenytoin),anti-viral, anti-HIV drug, anti-inflammatory, centrally-acting musclerelaxant, nootropica agent, apoptosis inhibitor, growth factor agonist,smooth muscle relaxantium, chloroquine, isoniazid, metronidazole,nitrofurantoin, thalidomide, etanercept, infliximab, leflunomide,dapsone, phenytoin, disulfiram, didanosine, stavudine, Kenalog-40,triamcinolone, Clinacort or antiparasitic. In some embodiments, themethod further comprises introducing, providing or administering to saidpatient the drug before, during or after administering the CGRP receptorantagonist. In some embodiments, the CGRP receptor antagonist is used incombination with the drug. In some embodiments, the method furthercomprises monitoring or measuring a level of nerve activity function insaid patient before, during or after administration of the effectiveamount of CGRP receptor antagonist. In some embodiments, the nerves areC-Nociceptors or Group C nerve fibers. In some embodiments the methodfurther comprises reducing pain associated with spontaneous nerveactivity in a patient in need thereof, by administration of a CGRPantagonist. In some embodiments, the CGRP receptor antagonist isadministered within a pharmaceutically acceptable formulation.

In a second aspect, a method of providing neuroprotection in a patientin need thereof is provided. The method comprises administering to thepatient an effective amount of CGRP receptor antagonist including apharmaceutically acceptable salt thereof. In some embodiments, the CGRPreceptor antagonist is a peptide comprising a structure of Formula I:

X¹—Y¹—Z¹   (I)

wherein X¹ is a modified N-terminal fragment (i.e. region) of calcitoningene-related peptide comprising from five to seven amino acid residues,wherein only two amino acid residues of the N-terminal fragment arecysteine (Cys), wherein the C-terminal residue of the fragment is Cys,and wherein the residue immediately preceding the C-terminal Cys residueof the region is a non-threonine substitution of a threonine (Thr)residue, Y¹ is a central core wherein at least one amino acid of thecentral core is arginine (Arg) or lysine (Lys) and the central corecomprises an α-helix, and Z¹ is a modified C-terminal fragment (i.e.region) of calcitonin gene-related peptide comprising from five to sevenamino acid residues with a C-terminal amide, where at least one aminoacid of the C-terminal fragment is phenylalanine (Phe), tyrosine (Tyr),proline (Pro) or hydroxyproline (Hyp). In some embodiments, the CGRPreceptor antagonist comprises a sequence set forth in one of SEQ ID NO:1(NH2-Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 2(NH2-Ala-Cys-Asp-Thr-Ala-Ser-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 3(NH2-Ala-Cys-Asp-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 4(NH2-Ala-Cys-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 5(NH2-Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 6(NH2-Ala-Cys-Arg-Phe-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 7(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 8(NH2-Cys-Ser-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 9(NH2-Ala-Cys-Asp-Thr-Ala-Leu-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 10(NH2-Ala-Cys-Asp-Thr-Ala-Ile-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 11(NH2-Ala-Cys-Asn-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 12(NH2-Cys-Ser-Asn-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 13(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2),SEQ ID NO: 14(Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Val-Asp-Pro-Ser-Ser-Pro-His-Ser-Tyr-NH2),SEQ ID NO: 15(Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Thr-His-Arg-Leu-Ala-Gly-Leu-Leu-Ser-Arg-Ser-Gly-Gly-Val-Val-Lys-Asn-Asn-Phe-Val-Pro-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 57(NH2-Ala-Cys-Asp-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or SEQ ID NO: 58(NH2-Ala-Cys-Asp-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or a pharmaceutically acceptable salt thereof. In some embodiments, theCGRP antagonist comprises a sequence selected from the group consistingof the sequences set forth in SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12 and 13. In some embodiments, the CGRP receptor antagonist isadministered topically, dermally, intradermally, subcutaneously, viadermal infusion, via subcutaneous infusion, intraocularly, buccally,intravenously, nasally, via inhalation, intramuscularly, sublingually ororally. In some embodiments, the effective amount comprises an amount ofabout 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 200 μg, 300 μg, 400 μg,500 μg, 600 μg, 700 μg, 800 μg, 900 μg, 1 mg, 5 mg, 10 mg, 40 mg, 50 mg,100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mgor 1000 mg or any amount in between a range defined by any twoaforementioned values. In some embodiments, the administering isperformed at least once daily, once a week, twice a week or three timesa week, or four times a week. In some embodiments, the patient issuffering from a nerve injury, neurodegenerative disease or a diseasesuch as cancer. In some embodiments, the nerve injury is from a physicalinjury, diabetes, cancer, diabetic neuropathy, head injury, seizures,infection, or ingestion of a pharmaceutical or a drug, such as achemotherapeutic. In some embodiments, the neurodegenerative disease isamyotrophic lateral sclerosis, multiple sclerosis, Creutzfeld-Jakobdisease, epilepsy, Parkinson's, Alzheimer's, glaucoma, cerebrovascularischemia, motor neuron disease, dementia, diabetic neuropathy,Huntington's disease, seizures or head injury. In some embodiments, thepatient has been identified or selected to receive neuroprotectiontreatment. In some embodiments, the method further comprises monitoringor measuring a level of nerve activity function in said patient before,during or after administration of the effective amount of CGRP receptorantagonist. In some embodiments, the patient has been identified orselected to receive a drug. In some embodiments, the drug is associatedwith side effects related to neuronal dysfunction. In some embodiments,the drug associated with neuronal dysfunction is a heart medication(i.e. almitrine), an anti-cancer drug, antibiotic (i.e. chlorampheticol,Cipro), anti-fungal, immunosuppressant drug (i.e. Cyclosporine), musclerelaxant (i.e. Hydrazaline), anti-seizure medications (i.e. Phenytoin),anti-viral, anti-HIV drug, anti-inflammatory, centrally-acting musclerelaxant, nootropica agent, apoptosis inhibitor, growth factor agonist,smooth muscle relaxantium, chloroquine, isoniazid, metronidazole,nitrofurantoin, thalidomide, etanercept, infliximab, leflunomide,dapsone, phenytoin, disulfiram, didanosine, stavudine, Kenalog-40,triamcinolone, Clinacort or antiparasitic. In some embodiments, the CGRPreceptor antagonist is administered within a pharmaceutically acceptableformulation. In some embodiments, the method further comprisesintroducing, providing or administering to said patient the drug before,during or after administering the CGRP receptor antagonist. In someembodiments, the CGRP receptor antagonist is used in combination withthe drug.

In a third aspect, a method of treating neuritis in a patient in needthereof is provided. The method comprises administering to the patientan effective amount of CGRP receptor antagonist or pharmaceuticallyacceptable salt thereof. In some embodiments, the CGRP receptorantagonist is a peptide or pharmaceutically acceptable salt thereofcomprising a structure of Formula I.

X¹—Y¹—Z¹   (I)

wherein X¹ is a modified N-terminal fragment (i.e. region) of calcitoningene-related peptide comprising from five to seven amino acid residues,wherein only two amino acid residues of the N-terminal fragment arecysteine (Cys), wherein the amino acid residue at the C-terminal end ofthe fragment (region) is Cys, and wherein the residue immediatelypreceding the C-terminal Cys residue is a non-threonine substitution ofthe threonine (Thr) residue found at position 6 of human CGRP, Y¹ is acentral core region wherein at least one amino acid of the central coreis arginine (Arg) or lysine (Lys) and the central core comprises anα-helix, and Z¹ is a modified C-terminal fragment (i.e. region) ofcalcitonin gene-related peptide comprising from five to seven amino acidresidues with a C-terminal amide, where at least one amino acid of theC-terminal fragment is phenylalanine (Phe), tyrosine (Tyr), proline(Pro) or hydroxyproline (Hyp). In some embodiments, the CGRP receptorantagonist is a peptide comprising a sequence set forth in one of SEQ IDNO: 1(NH2-Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 2(NH2-Ala-Cys-Asp-Thr-Ala-Ser-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 3(NH2-Ala-Cys-Asp-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 4(NH2-Ala-Cys-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 5(NH2-Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 6(NH2-Ala-Cys-Arg-Phe-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 7(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 8(NH2-Cys-Ser-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 9(NH2-Ala-Cys-Asp-Thr-Ala-Leu-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 10(NH2-Ala-Cys-Asp-Thr-Ala-Ile-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 11(NH2-Ala-Cys-Asn-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 12(NH2-Cys-Ser-Asn-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 13(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2),SEQ ID NO: 14(Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Val-Asp-Pro-Ser-Ser-Pro-His-Ser-Tyr-NH2),SEQ ID NO: 15(Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Thr-His-Arg-Leu-Ala-Gly-Leu-Leu-Ser-Arg-Ser-Gly-Gly-Val-Val-Lys-Asn-Asn-Phe-Val-Pro-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 57(NH2-Ala-Cys-Asp-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or SEQ ID NO: 58(NH2-Ala-Cys-Asp-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or a pharmaceutically acceptable salt thereof. In some embodiments, theCGRP antagonist comprises a sequence selected from the group consistingof the sequences set forth in SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12 and 13. In some embodiments, the CGRP receptor antagonist isadministered topically, dermally, intradermally, subcutaneously, viadermal infusion, via subcutaneous infusion, intraocularly, buccally,intravenously, nasally, via inhalation, intramuscularly, sublingually ororally. In some embodiments, the effective amount comprises an amount ofabout 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 200 μg, 300 μg, 400 μg,500 μg, 600 μg, 700 μg, 800 μg, 900 μg, 1 mg, 5 mg, 10 mg, 40 mg, 50 mg,100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mgor 1000 mg or any amount in between a range defined by any twoaforementioned values. In some embodiments, the administering isperformed at least once daily, once a week, twice a week or three timesa week, or four times a week. In some embodiments, the method furthercomprises monitoring or measuring a level of nerve activity function insaid patient before, during or after administration of the effectiveamount of CGRP receptor antagonist. In some embodiments, the patient hasbeen identified or selected to receive a drug. In some embodiments thedrug can cause neuronal dysfunction. In some embodiments, the neuritisis from a physical injury, vascular injury, toxin, aging, a geneticdisorder, infection (viral or bacterial), diphtheria, herpes zoster(shingles), leprosy, Lyme disease, chemical injury such as chemotherapy,radiation therapy, alcoholism, autoimmune disease, multiple sclerosis,Guillain-Barre syndrome, beriberi (vitamin B1 deficiency), cancer,Celiac disease, diabetes (Diabetic neuropathy), hypothyroidism,porphyria, vitamin B12 deficiency, vitamin B6 excess, brachial neuritis,cranial neuritis, Bell's palsy, optic neuritis or vestibular neuritis.In some embodiments, the CGRP receptor antagonist is administered withina pharmaceutically acceptable formulation. In some embodiments, the drugcausing neuronal dysfunction is a heart medication (i.e. almitrine), ananti-cancer drug, antibiotic (i.e. chlorampheticol, Cipro), anti-fungal,immunosuppressant drug (i.e. Cyclosporine), muscle relaxant (i.e.Hydrazaline), anti-seizure medications (i.e. Phenytoin), anti-viral,anti-HIV drug, anti-inflammatory, centrally-acting muscle relaxant,nootropica agent, apoptosis inhibitor, growth factor agonist, smoothmuscle relaxantium, chloroquine, isoniazid, metronidazole,nitrofurantoin, thalidomide, etanercept, infliximab, leflunomide,dapsone, phenytoin, disulfiram, didanosine, stavudine, Kenalog-40,triamcinolone, Clinacort or antiparasitic. In some embodiments, themethod further comprises introducing, providing or administering to saidpatient the drug before, during or after administering the CGRP receptorantagonist.

In a fourth aspect, a method of treating glaucoma in a patient isprovided. The method comprises administering to the patient an effectiveamount of CGRP receptor antagonist or pharmaceutically acceptable saltthereof. In some embodiments, the CGRP receptor antagonist is a peptideor pharmaceutically acceptable salt thereof comprising a structure ofFormula I.

X¹—Y¹—Z¹   (I)

wherein X¹ is a modified N-terminal fragment (i.e., region) ofcalcitonin gene-related peptide comprising from five to seven amino acidresidues, wherein only two amino acid residues of the N-terminalfragment are cysteine (Cys), wherein the residue at the C-terminal endof the fragment is Cys, and wherein the residue immediately precedingthe C-terminal Cys residue of the region is a non-threonine substitutionof the threonine (Thr) residue of position 6 of human CGRP, Y¹ is acentral core region wherein at least one amino acid of the central coreis arginine (Arg) or lysine (Lys) and the central core comprises anα-helix and Z¹ is a modified C-terminal fragment (i.e. region) ofcalcitonin gene-related peptide comprising from five to seven amino acidresidues with a C-terminal amide, where at least one amino acid of theC-terminal region is phenylalanine (Phe), tyrosine (Tyr), proline (Pro)or hydroxyproline (Hyp). In some embodiments, the CGRP receptorantagonist is a peptide comprising a sequence set forth in one of SEQ IDNO: 1(NH2-Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 2(NH2-Ala-Cys-Asp-Thr-Ala-Ser-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 3(NH2-Ala-Cys-Asp-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 4(NH2-Ala-Cys-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 5(NH2-Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 6(NH2-Ala-Cys-Arg-Phe-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 7(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 8(NH2-Cys-Ser-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 9(NH2-Ala-Cys-Asp-Thr-Ala-Leu-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 10(NH2-Ala-Cys-Asp-Thr-Ala-Ile-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 11(NH2-Ala-Cys-Asn-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 12(NH2-Cys-Ser-Asn-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 13(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2),SEQ ID NO: 14(Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Val-Asp-Pro-Ser-Ser-Pro-His-Ser-Tyr-NH2),SEQ ID NO: 15(Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Thr-His-Arg-Leu-Ala-Gly-Leu-Leu-Ser-Arg-Ser-Gly-Gly-Val-Val-Lys-Asn-Asn-Phe-Val-Pro-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 57(NH2-Ala-Cys-Asp-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or SEQ ID NO: 58(NH2-Ala-Cys-Asp-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or a pharmaceutically acceptable salt thereof. In some embodiments, theCGRP antagonist comprises a sequence selected from the group consistingof the sequences set forth in SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12 and 13. In some embodiments, the CGRP receptor antagonist isadministered topically, dermally, intradermally, subcutaneously, viadermal infusion, via subcutaneous infusion, intraocularly, buccally,intravenously, nasally via inhalation, intramuscularly, sublingually ororally. In some embodiments, wherein the effective amount comprises anamount of about 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 200 μg, 300μg, 400 μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg, 1 mg, 10 mg, 20 mg,30 mg, 40 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700mg, 800 mg, 900 mg or 1000 mg or any amount in between a range definedby any two aforementioned values. In some embodiments, the administeringis performed at least four times a day, three times a day, two times aday, or once a day. In some embodiments, the patient has diabetes. Insome embodiments, the patient has been identified or selected to receivea drug for glaucoma. In some embodiments, the drug can cause nerve orcentral nervous system damage or neuronal dysfunction (i.e. betablocker). In some embodiments, the CGRP receptor antagonist isadministered within a pharmaceutically acceptable formulation. In someembodiments, the method further comprises introducing, providing oradministering to said patient the drug before, during or afteradministering the CGRP receptor antagonist. In some embodiments, theCGRP receptor antagonist is used in combination with the drug.

In a fifth aspect, a method of reducing LDL in a patient in need thereofis provided. The method comprises administering to the patient aneffective amount of CGRP receptor antagonist or pharmaceuticallyacceptable salt thereof. In some embodiments, the CGRP receptorantagonist is a peptide or pharmaceutically acceptable salt thereofcomprising a structure of Formula I:

X¹—Y¹—Z¹   (I)

wherein X¹ is a modified N-terminal fragment (i.e., region) ofcalcitonin gene-related peptide comprising from five to seven amino acidresidues, wherein only two amino acid residues of the N-terminalfragment are cysteine (Cys), wherein the residue at the C-terminal endof the region is Cys, and wherein the residue immediately preceding theC-terminal Cys residue of the region is a non-threonine substitution ofthe threonine (Thr) residue of position 6 of human GCRP, Y¹ is a centralcore region wherein at least one amino acid of the central core isarginine (Arg) or lysine (Lys) and the central core comprises an α-helixand Z¹ is a modified C-terminal fragment (i.e., region) of calcitoningene-related peptide comprising from five to seven amino acid residueswith a C-terminal amide, where at least one amino acid of the C-terminalfragment is phenylalanine (Phe), tyrosine (Tyr), proline (Pro) orhydroxyproline (Hyp). In some embodiments, the CGRP receptor antagonistis a peptide comprising a sequence set forth in one of SEQ ID NO: 1(NH2-Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 2(NH2-Ala-Cys-Asp-Thr-Ala-Ser-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 3(NH2-Ala-Cys-Asp-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 4(NH2-Ala-Cys-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 5(NH2-Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 6(NH2-Ala-Cys-Arg-Phe-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 7(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 8(NH2-Cys-Ser-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 9(NH2-Ala-Cys-Asp-Thr-Ala-Leu-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 10(NH2-Ala-Cys-Asp-Thr-Ala-Ile-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 11(NH2-Ala-Cys-Asn-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 12(NH2-Cys-Ser-Asn-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 13(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2),SEQ ID NO: 14(Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Val-Asp-Pro-Ser-Ser-Pro-His-Ser-Tyr-NH2),SEQ ID NO: 15(Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Thr-His-Arg-Leu-Ala-Gly-Leu-Leu-Ser-Arg-Ser-Gly-Gly-Val-Val-Lys-Asn-Asn-Phe-Val-Pro-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 57(NH2-Ala-Cys-Asp-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or SEQ ID NO: 58(NH2-Ala-Cys-Asp-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or a pharmaceutically acceptable salt thereof. In some embodiments, theCGRP antagonist comprises a sequence selected from the group consistingof the sequences set forth in SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12 and 13. In some embodiments, the patient is suffering from highLDL concentration in the blood. In some embodiments, the method furthercomprises monitoring or measuring the level or amount of LDL in saidpatient before, during, or after administration of the effective amountof CGRP receptor antagonist. In some embodiments, the patient is a male.In some embodiments, the patient has familial hypercholesterolemia. Insome embodiments, the CGRP receptor antagonist is administered dermally,intradermally, subcutaneously, via dermal infusion, via subcutaneousinfusion, intravenously, buccally, intramuscularly, sublingually ororally. In some embodiments, wherein the effective amount comprises anamount of about 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 200 μg, 300μg, 400 μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg, 1 mg, 10 mg, 20 mg,30 mg, 40 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700mg, 800 mg, 900 mg or 1000 mg or any amount in between a range definedby any two aforementioned values. In some embodiments, the administeringis performed at least four times a day, three times a day, two times aday, or once a day.

In a sixth aspect, a method of protecting a patient from nerve damage ornerve inflammation is provided. The method comprises administering tothe patient an effective amount of CGRP receptor antagonist orpharmaceutically acceptable salt thereof. In some embodiments, thepatient suffers from a post ischemic event. In some embodiments, theCGRP receptor antagonist is a peptide or a pharmaceutically acceptablesalt thereof comprising a structure of Formula I:

X¹—Y¹—Z¹   (I)

wherein X¹ is a modified N-terminal fragment (i.e., region) ofcalcitonin gene-related peptide comprising from five to seven amino acidresidues, wherein only two amino acid residues of the N-terminalfragment are cysteine (Cys), wherein the residue at the C-terminal endof the region is Cys, and wherein the residue immediately preceding theC-terminal Cys residue of the region is a non-threonine substitution ofthe threonine (Thr) residue of position 6 of human CGRP, Y¹ is a centralcore region wherein at least one amino acid of the central core isarginine (Arg) or lysine (Lys) and the central core comprises an α-helixand Z¹ is a modified C-terminal fragment (i.e., region) of calcitoningene-related peptide comprising from five to seven amino acid residueswith a C-terminal amide, where at least one amino acid of the Z1 regionis phenylalanine (Phe), tyrosine (Tyr), proline (Pro) or hydroxyproline(Hyp). In some embodiments, the CGRP receptor antagonist is a peptidecomprising a sequence set forth in one of SEQ ID NO: 1(NH2-Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 2(NH2-Ala-Cys-Asp-Thr-Ala-Ser-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 3(NH2-Ala-Cys-Asp-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 4(NH2-Ala-Cys-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 5(NH2-Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 6(NH2-Ala-Cys-Arg-Phe-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 7(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 8(NH2-Cys-Ser-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 9(NH2-Ala-Cys-Asp-Thr-Ala-Leu-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 10(NH2-Ala-Cys-Asp-Thr-Ala-Ile-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 11(NH2-Ala-Cys-Asn-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 12(NH2-Cys-Ser-Asn-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 13(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2),SEQ ID NO: 14(Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Val-Asp-Pro-Ser-Ser-Pro-His-Ser-Tyr-NH2),SEQ ID NO: 15(Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Thr-His-Arg-Leu-Ala-Gly-Leu-Leu-Ser-Arg-Ser-Gly-Gly-Val-Val-Lys-Asn-Asn-Phe-Val-Pro-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 57(NH2-Ala-Cys-Asp-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or SEQ ID NO: 58(NH2-Ala-Cys-Asp-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or a pharmaceutically acceptable salt thereof. In some embodiments, theCGRP antagonist comprises a sequence selected from the group consistingof the sequences set forth in SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12 and 13. In some embodiments, the CGRP receptor antagonist isadministered topically, dermally, intradermally, subcutaneously, viadermal infusion, via subcutaneous infusion, intraocularly, buccally,intravenously, nasally, via inhalation, intramuscularly, sublingually ororally. In some embodiments, the effective amount comprises an amount ofabout 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 200 μg, 300 μg, 400 μg,500 μg, 600 μg, 700 μg, 800 μg, 900 μg, 1 mg, 10 mg, 20 mg, 30 mg, 40mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800mg, 900 mg or 1000 mg or any amount in between a range defined by anytwo aforementioned values. In some embodiments, the administering isperformed at least four times a day, three times a day, two times a day,or once a day.

In a seventh aspect, an effective amount of calcitonin gene-relatedpeptide (CGRP) receptor antagonist, or a pharmaceutically acceptablesalt thereof is provided, for use in reducing spontaneous nerve activityof nerves in a patient in need thereof. In some embodiments of thecalcitonin gene-related peptide (CGRP) receptor antagonist for use, theCGRP receptor antagonist is a peptide comprising a structure of FormulaI:

X1-Y1-Z1   (I)

wherein:

X1 is a modified N-terminal fragment (i.e., region) of calcitoningene-related peptide comprising from five to seven amino acid residues,wherein only two amino acid residues of the N-terminal fragment arecysteine (Cys), wherein the residue at the C-terminal end of the regionis Cys, and wherein the residue immediately preceding the C-terminal Cysresidue of the region is a non-threonine substitution of the threonine(Thr) residue of position 6 of human CGRP;

Y1 is a central core region wherein at least one amino acid of thecentral core is arginine (Arg) or lysine (Lys) and the central corecomprises an α-helix; and

Z1 is a modified C-terminal fragment (i.e., region) of calcitoningene-related peptide comprising from five to seven amino acid residueswith a C-terminal amide, where at least one amino acid of the C-terminalfragment is phenylalanine (Phe), tyrosine (Tyr), proline (Pro) orhydroxyproline (Hyp). In some embodiments of the calcitonin gene-relatedpeptide (CGRP) receptor antagonist for use, the CGRP receptor antagonistcomprises a sequence set forth in one of SEQ ID NO: 1(NH2-Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 2(NH2-Ala-Cys-Asp-Thr-Ala-Ser-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 3(NH2-Ala-Cys-Asp-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 4(NH2-Ala-Cys-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 5(NH2-Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 6(NH2-Ala-Cys-Arg-Phe-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 7(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 8(NH2-Cys-Ser-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 9(NH2-Ala-Cys-Asp-Thr-Ala-Leu-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 10(NH2-Ala-Cys-Asp-Thr-Ala-Ile-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 11(NH2-Ala-Cys-Asn-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 12(NH2-Cys-Ser-Asn-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 13(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2),SEQ ID NO: 14(Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Val-Asp-Pro-Ser-Ser-Pro-His-Ser-Tyr-NH2),SEQ ID NO: 15(Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Thr-His-Arg-Leu-Ala-Gly-Leu-Leu-Ser-Arg-Ser-Gly-Gly-Val-Val-Lys-Asn-Asn-Phe-Val-Pro-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 57(NH2-Ala-Cys-Asp-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or SEQ ID NO: 58(NH2-Ala-Cys-Asp-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or a pharmaceutically acceptable salt thereof. In some embodiments ofthe calcitonin gene-related peptide (CGRP) receptor antagonist for use,the CGRP receptor antagonist comprises a sequence selected from thegroup consisting of the sequences set forth in SEQ ID NO: 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12 and 13. In some embodiments of the calcitoningene-related peptide (CGRP) receptor antagonist for use, the CGRPreceptor antagonist is administered topically, dermally, intradermally,subcutaneously, via dermal infusion, via subcutaneous infusion,intraocularly, buccally, intravenously, nasally, via inhalation,intramuscularly, sublingually or orally. In some embodiments of thecalcitonin gene-related peptide (CGRP) receptor antagonist for use, theCGRP receptor antagonist for use is in a pharmaceutical vehicleformulated for topical, dermal, intradermal, subcutaneous, dermalinfusion, subcutaneous infusion, intraocular, buccal, intravenous,nasal, inhalation, intramuscular, sublingual or oral administration. Insome embodiments of the calcitonin gene-related peptide (CGRP) receptorantagonist for use, the effective amount of calcitonin gene-related(CGRP) comprises an amount of about 50 μg, 60 μg, 70 μg, 80 μg, 90 μg,100 μg, 200 μg, 300 μg, 400 μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg,1 mg, 5 mg, 10 mg, 40 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg,600 mg, 700 mg, 800 mg, 900 mg or 1000 mg or any amount in between arange defined by any two aforementioned values. In some embodiments ofthe calcitonin gene-related peptide (CGRP) receptor antagonist for use,the calcitonin gene-related peptide (CGRP) receptor antagonist isadministered at least once daily, once a week, twice a week, three timesa week, or four times a week. In some embodiments of the calcitoningene-related peptide (CGRP) receptor antagonist for use, the spontaneousnerve activity is due to a nerve injury or neurodegenerative disease. Insome embodiments of the calcitonin gene-related peptide (CGRP) receptorantagonist for use, the nerve injury is from a physical injury,diabetes, cancer, diabetic neuropathy, head injury, seizures, infection,or ingestion of a pharmaceutical or drug, such as a chemotherapeutic. Insome embodiments of the calcitonin gene-related peptide (CGRP) receptorantagonist for use, the neurodegenerative disease is amyotrophic lateralsclerosis, multiple sclerosis, Creutzfeld-Jakob disease, epilepsy,Parkinson's, Alzheimer's, glaucoma, cerebrovascular ischemia, motorneuron disease, dementia, diabetic neuropathy or Huntington's disease.In some embodiments of the calcitonin gene-related peptide (CGRP)receptor antagonist for use, the patient has been identified or selectedto receive a drug for neurodegenerative diseases, neurovascular disorderor disease such as cancer. In some embodiments of the calcitoningene-related peptide (CGRP) receptor antagonist for use, the nerveinjury is from a pharmaceutical or drug, wherein the pharmaceutical ordrug is a heart medication (i.e. almitrine), an anti-cancer drug,antibiotic (i.e. chlorampheticol, Cipro), anti-fungal, immunosuppressantdrug (i.e. Cyclosporine), muscle relaxant (i.e. Hydrazaline),anti-seizure medications (i.e. Phenytoin), anti-viral, anti-HIV drug,anti-inflammatory, centrally-acting muscle relaxant, nootropica agent,apoptosis inhibitor, growth factor agonist, smooth muscle relaxantium,chloroquine, isoniazid, metronidazole, nitrofurantoin, thalidomide,etanercept, infliximab, leflunomide, dapsone, phenytoin, disulfiram,didanosine, stavudine, Kenalog-40, triamcinolone, Clinacort orantiparasitic. In some embodiments of the calcitonin gene-relatedpeptide (CGRP) receptor antagonist for use, the drug is administered tosaid patient before, during or after administering the CGRP receptorantagonist. In some embodiments of the calcitonin gene-related peptide(CGRP) receptor antagonist for use, the CGRP receptor antagonist is usedin combination with the drug. In some embodiments of the calcitoningene-related peptide (CGRP) receptor antagonist for use, a level ofnerve activity function is monitored or measured in said patient before,during or after administration of the effective amount of CGRP receptorantagonist. In some embodiments of the calcitonin gene-related peptide(CGRP) receptor antagonist for use, the nerves are C-Nociceptors orGroup C nerve fibers. In some embodiments of the calcitonin gene-relatedpeptide (CGRP) receptor antagonist for use, the calcitonin gene-relatedpeptide (CGRP) receptor antagonist reduces pain associated withspontaneous nerve activity in the patient in need thereof. In someembodiments of the calcitonin gene-related peptide (CGRP) receptorantagonist for use, the CGRP receptor antagonist is administered withina pharmaceutically acceptable formulation.

In an eighth aspect, an effective amount of calcitonin gene-relatedpeptide (CGRP) receptor antagonist or pharmaceutically acceptable saltthereof, for use in providing neuroprotection in a patient in needthereof, is provided. In some embodiments of the calcitonin gene-relatedpeptide (CGRP) receptor antagonist for use, the CGRP receptor antagonistis a peptide comprising a structure of Formula I:

X1-Y1-Z1   (I)

wherein:

X1 is a modified N-terminal fragment (i.e. region) of calcitoningene-related peptide comprising from five to seven amino acid residues,wherein only two amino acid residues of the N-terminal fragment arecysteine (Cys), wherein the C-terminal residue of the fragment is Cys,and wherein the residue immediately preceding the C-terminal Cys residueof the region is a non-threonine substitution of a threonine (Thr)residue;

Y1 is a central core wherein at least one amino acid of the central coreis arginine (Arg) or lysine (Lys) and the central core comprises anα-helix; and

Z¹ is a modified C-terminal fragment (i.e. region) of calcitoningene-related peptide comprising from five to seven amino acid residueswith a C-terminal amide, where at least one amino acid of the C-terminalfragment is phenylalanine (Phe), tyrosine (Tyr), proline (Pro) orhydroxyproline (Hyp). In some embodiments of the calcitonin gene-relatedpeptide (CGRP) receptor antagonist for use, the CGRP receptor antagonistcomprises a sequence set forth in one of SEQ ID NO: 1(NH2-Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 2(NH2-Ala-Cys-Asp-Thr-Ala-Ser-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 3(NH2-Ala-Cys-Asp-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 4(NH2-Ala-Cys-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 5(NH2-Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 6(NH2-Ala-Cys-Arg-Phe-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 7(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 8(NH2-Cys-Ser-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 9(NH2-Ala-Cys-Asp-Thr-Ala-Leu-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 10(NH2-Ala-Cys-Asp-Thr-Ala-Ile-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 11(NH2-Ala-Cys-Asn-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 12(NH2-Cys-Ser-Asn-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 13(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2),SEQ ID NO: 14(Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Val-Asp-Pro-Ser-Ser-Pro-His-Ser-Tyr-NH2),SEQ ID NO: 15(Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Thr-His-Arg-Leu-Ala-Gly-Leu-Leu-Ser-Arg-Ser-Gly-Gly-Val-Val-Lys-Asn-Asn-Phe-Val-Pro-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 57(NH2-Ala-Cys-Asp-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or SEQ ID NO: 58(NH2-Ala-Cys-Asp-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or a pharmaceutically acceptable salt thereof. In some embodiments ofthe calcitonin gene-related peptide (CGRP) receptor antagonist for use,the CGRP antagonist comprises a sequence selected from the groupconsisting of the sequences set forth in SEQ ID NO: 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12 and 13. In some embodiments of the calcitoningene-related peptide (CGRP) receptor antagonist for use, the CGRPreceptor antagonist is administered topically, dermally, intradermally,subcutaneously, via dermal infusion, via subcutaneous infusion,intraocularly, buccally, intravenously, nasally, via inhalation,intramuscularly, sublingually or orally. In some embodiments of thecalcitonin gene-related peptide (CGRP) receptor antagonist for use, theCGRP receptor antagonist is in a pharmaceutical vehicle formulated fortopical, dermal, intradermal, subcutaneous, dermal infusion,subcutaneous infusion, intraocular, buccal, intravenous, nasal,inhalation, intramuscular, sublingual or oral administration. In someembodiments of the calcitonin gene-related peptide (CGRP) receptorantagonist for use, the effective amount comprises an amount of about 50μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 200 μg, 300 μg, 400 μg, 500 μg,600 μg, 700 μg, 800 μg, 900 μg, 1 mg, 5 mg, 10 mg, 40 mg, 50 mg, 100 mg,200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000mg or any amount in between a range defined by any two aforementionedvalues. In some embodiments of the calcitonin gene-related peptide(CGRP) receptor antagonist for use, the calcitonin gene-related peptide(CGRP) receptor antagonist is administered at least once daily, once aweek, twice a week, three times a week, or four times a week. In someembodiments of the calcitonin gene-related peptide (CGRP) receptorantagonist for use, the patient is suffering from a nerve injury,neurodegenerative disease or a disease such as cancer. In someembodiments of the calcitonin gene-related peptide (CGRP) receptorantagonist for use, the nerve injury is from a physical injury,diabetes, cancer, diabetic neuropathy, head injury, seizures, infection,or ingestion of a pharmaceutical or drug, such as a chemotherapeutic. Insome embodiments of the calcitonin gene-related peptide (CGRP) receptorantagonist for use, the pharmaceutical or drug is associated with sideeffects related to neuronal dysfunction. In some embodiments of thecalcitonin gene-related peptide (CGRP) receptor antagonist for use, theneurodegenerative disease is amyotrophic lateral sclerosis, multiplesclerosis, Creutzfeld-Jakob disease, epilepsy, Parkinson's, Alzheimer's,glaucoma, cerebrovascular ischemia, motor neuron disease, dementia,diabetic neuropathy, Huntington's disease, seizures or head injury. Insome embodiments of the calcitonin gene-related peptide (CGRP) receptorantagonist for use, the patient has been identified or selected toreceive neuroprotection treatment. In some embodiments of the calcitoningene-related peptide (CGRP) receptor antagonist for use, a level ofnerve activity function is monitored or measured in said patient before,during or after administration of the effective amount of CGRP receptorantagonist. In some embodiments of the calcitonin gene-related peptide(CGRP) receptor antagonist for use, the patient has been identified orselected to receive a drug. In some embodiments of the calcitoningene-related peptide (CGRP) receptor antagonist for use, the drug isassociated with side effects related to neuronal dysfunction. In someembodiments of the calcitonin gene-related peptide (CGRP) receptorantagonist for use, the drug associated with neuronal dysfunction is aheart medication (i.e. almitrine), an anti-cancer drug, antibiotic (i.e.chlorampheticol, Cipro), anti-fungal, immunosuppressant drug (i.e.Cyclosporine), muscle relaxant (i.e. Hydrazaline), anti-seizuremedications (i.e. Phenytoin), anti-viral, anti-HIV drug,anti-inflammatory, centrally-acting muscle relaxant, nootropica agent,apoptosis inhibitor, growth factor agonist, smooth muscle relaxantium,chloroquine, isoniazid, metronidazole, nitrofurantoin, thalidomide,etanercept, infliximab, leflunomide, dapsone, phenytoin, disulfiram,didanosine, stavudine, Kenalog-40, triamcinolone, Clinacort orantiparasitic. In some embodiments of the calcitonin gene-relatedpeptide (CGRP) receptor antagonist for use, the CGRP receptor antagonistis administered within a pharmaceutically acceptable formulation. Insome embodiments of the calcitonin gene-related peptide (CGRP) receptorantagonist for use, the drug is introduced, provided or administered tosaid patient before, during or after administering the CGRP receptorantagonist. In some embodiments of the calcitonin gene-related peptide(CGRP) receptor antagonist for use, the CGRP receptor antagonist is usedin combination with the drug.

In a ninth aspect, an effective amount of calcitonin gene-relatedpeptide (CGRP) receptor antagonist or pharmaceutically acceptable saltthereof, for use in treating neuritis in a patient in need thereof isprovided. In some embodiments of the calcitonin gene-related peptide(CGRP) receptor antagonist for use, the CGRP receptor antagonist orpharmaceutically acceptable salt thereof comprises a structure ofFormula I:

X1-Y1-Z1   (I)

wherein:

X1 is a modified N-terminal fragment (i.e. region) of calcitoningene-related peptide comprising from five to seven amino acid residues,wherein only two amino acid residues of the N-terminal fragment arecysteine (Cys), wherein the amino acid residue at the C-terminal end ofthe fragment (region) is Cys, and wherein the residue immediatelypreceding the C-terminal Cys residue is a non-threonine substitution ofthe threonine (Thr) residue found at position 6 of human CGRP;

Y1 is a central core region wherein at least one amino acid of thecentral core is arginine (Arg) or lysine (Lys) and the central corecomprises an α-helix; and

Z¹ is a modified C-terminal fragment (i.e. region) of calcitoningene-related peptide comprising from five to seven amino acid residueswith a C-terminal amide, where at least one amino acid of the C-terminalfragment is phenylalanine (Phe), tyrosine (Tyr), proline (Pro) orhydroxyproline (Hyp). In some embodiments of the calcitonin gene-relatedpeptide (CGRP) receptor antagonist for use, the CGRP receptor antagonistcomprises a sequence set forth in one of SEQ ID NO: 1(NH2-Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 2(NH2-Ala-Cys-Asp-Thr-Ala-Ser-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 3(NH2-Ala-Cys-Asp-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 4(NH2-Ala-Cys-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 5(NH2-Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 6(NH2-Ala-Cys-Arg-Phe-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 7(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 8(NH2-Cys-Ser-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 9(NH2-Ala-Cys-Asp-Thr-Ala-Leu-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 10(NH2-Ala-Cys-Asp-Thr-Ala-Ile-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 11(NH2-Ala-Cys-Asn-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 12(NH2-Cys-Ser-Asn-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 13(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2),SEQ ID NO: 14(Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Val-Asp-Pro-Ser-Ser-Pro-His-Ser-Tyr-NH2),SEQ ID NO: 15(Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Thr-His-Arg-Leu-Ala-Gly-Leu-Leu-Ser-Arg-Ser-Gly-Gly-Val-Val-Lys-Asn-Asn-Phe-Val-Pro-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 57(NH2-Ala-Cys-Asp-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or SEQ ID NO: 58(NH2-Ala-Cys-Asp-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or a pharmaceutically acceptable salt thereof. In some embodiments ofthe calcitonin gene-related peptide (CGRP) receptor antagonist for use,the CGRP antagonist comprises a sequence selected from the groupconsisting of the sequences set forth in SEQ ID NO: 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12 and 13. In some embodiments of the calcitoningene-related peptide (CGRP) receptor antagonist for use, the CGRPreceptor antagonist is administered topically, dermally, intradermally,subcutaneously, via dermal infusion, via subcutaneous infusion,intraocularly, buccally, intravenously, nasally, via inhalation,intramuscularly, sublingually or orally. In some embodiments of thecalcitonin gene-related peptide (CGRP) receptor antagonist for use, theCGRP receptor antagonist is in a pharmaceutical vehicle formulated fortopical, dermal, intradermal, subcutaneous, dermal infusion,subcutaneous infusion, intraocular, buccal, intravenous, nasal,inhalation, intramuscular, sublingual or oral administration. In someembodiments of the calcitonin gene-related peptide (CGRP) receptorantagonist for use, the effective amount comprises an amount of 50 μg,60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 200 μg, 300 μg, 400 μg, 500 μg, 600μg, 700 μg, 800 μg, 900 μg, 1 mg, 5 mg, 10 mg, 40 mg, 50 mg, 100 mg, 200mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg orany amount in between a range defined by any two aforementioned values.In some embodiments of the calcitonin gene-related peptide (CGRP)receptor antagonist for use, the calcitonin gene-related peptide (CGRP)receptor antagonist is administered at least once daily, once a week,twice a week, three times a week, or four times a week. In someembodiments of the calcitonin gene-related peptide (CGRP) receptorantagonist for use, a level of nerve activity function is monitored ormeasured in said patient before, during or after administration of theeffective amount of CGRP receptor antagonist. In some embodiments of thecalcitonin gene-related peptide (CGRP) receptor antagonist for use, thepatient has been identified or selected to receive a drug. In someembodiments of the calcitonin gene-related peptide (CGRP) receptorantagonist for use, the drug can cause neuronal dysfunction. In someembodiments of the calcitonin gene-related peptide (CGRP) receptorantagonist for use, the drug causing neuronal dysfunction is a heartmedication (i.e. almitrine), an anti-cancer drug, antibiotic (i.e.chlorampheticol, Cipro), anti-fungal, immunosuppressant drug (i.e.Cyclosporine), muscle relaxant (i.e. Hydrazaline), anti-seizuremedications (i.e. Phenytoin), anti-viral, anti-HIV drug,anti-inflammatory, centrally-acting muscle relaxant, nootropica agent,apoptosis inhibitor, growth factor agonist, smooth muscle relaxantium,chloroquine, isoniazid, metronidazole, nitrofurantoin, thalidomide,etanercept, infliximab, leflunomide, dapsone, phenytoin, disulfiram,didanosine, stavudine, Kenalog-40, triamcinolone, Clinacort orantiparasitic. In some embodiments of the calcitonin gene-relatedpeptide (CGRP) receptor antagonist for use, the neuritis is from aphysical injury, vascular injury, toxin aging, a genetic disorder,infection (viral or bacterial), diphtheria, herpes zoster (shingles),leprosy, Lyme disease, chemical injury such as chemotherapy, radiationtherapy, alcoholism, autoimmune disease, multiple sclerosis,Guillain-Barre syndrome, beriberi (vitamin B1 deficiency), cancer,Celiac disease, diabetes (Diabetic neuropathy), hypothyroidism,porphyria, vitamin B12 deficiency, vitamin B6 excess, brachial neuritis,cranial neuritis, Bell's palsy, optic neuritis or vestibular neuritis.In some embodiments of the calcitonin gene-related peptide (CGRP)receptor antagonist for use, the CGRP receptor antagonist isadministered within a pharmaceutically acceptable formulation. In someembodiments of the calcitonin gene-related peptide (CGRP) receptorantagonist for use, the drug is administered before, during or afteradministering the CGRP receptor antagonist.

In a tenth aspect, an effective amount of calcitonin gene-relatedpeptide (CGRP) receptor antagonist or pharmaceutically acceptable saltthereof for use in treating glaucoma in a patient, provided. In someembodiments of the calcitonin gene-related peptide (CGRP) receptorantagonist for use, the CGRP receptor antagonist is a peptide orpharmaceutically acceptable salt thereof comprising a structure ofFormula I:

X1-Y1-Z1   (I)

wherein:

X1 is a modified N-terminal fragment (i.e., region) of calcitoningene-related peptide comprising from five to seven amino acid residues,wherein only two amino acid residues of the N-terminal fragment arecysteine (Cys), wherein the residue at the C-terminal end of thefragment is Cys, and wherein the residue immediately preceding theC-terminal Cys residue of the region is a non-threonine substitution ofthe threonine (Thr) residue of position 6 of human CGRP;

Y1 is a central core region wherein at least one amino acid of thecentral core is arginine (Arg) or lysine (Lys) and the central corecomprises an α-helix; and

Z¹ is a modified C-terminal fragment (i.e. region) of calcitoningene-related peptide comprising from five to seven amino acid residueswith a C-terminal amide, where at least one amino acid of the C-terminalregion is phenylalanine (Phe), tyrosine (Tyr), proline (Pro) orhydroxyproline (Hyp). In some embodiments of the calcitonin gene-relatedpeptide (CGRP) receptor antagonist for use, the CGRP receptor antagonistcomprises a sequence set forth in one of SEQ ID NO: 1(NH2-Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 2(NH2-Ala-Cys-Asp-Thr-Ala-Ser-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 3(NH2-Ala-Cys-Asp-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 4(NH2-Ala-Cys-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 5(NH2-Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 6(NH2-Ala-Cys-Arg-Phe-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 7(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 8(NH2-Cys-Ser-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 9(NH2-Ala-Cys-Asp-Thr-Ala-Leu-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 10(NH2-Ala-Cys-Asp-Thr-Ala-Ile-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 11(NH2-Ala-Cys-Asn-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 12(NH2-Cys-Ser-Asn-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 13(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2),SEQ ID NO: 14(Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Val-Asp-Pro-Ser-Ser-Pro-His-Ser-Tyr-NH2),SEQ ID NO: 15(Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Thr-His-Arg-Leu-Ala-Gly-Leu-Leu-Ser-Arg-Ser-Gly-Gly-Val-Val-Lys-Asn-Asn-Phe-Val-Pro-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 57(NH2-Ala-Cys-Asp-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or SEQ ID NO: 58(NH2-Ala-Cys-Asp-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or a pharmaceutically acceptable salt thereof. In some embodiments ofthe calcitonin gene-related peptide (CGRP) receptor antagonist for use,the CGRP antagonist comprises a sequence selected from the groupconsisting of the sequences set forth in SEQ ID NO: 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12 and 13. In some embodiments of the calcitoningene-related peptide (CGRP) receptor antagonist for use, the CGRPreceptor antagonist is administered topically, dermally, intradermally,subcutaneously, via dermal infusion, via subcutaneous infusion,intraocularly, buccally, intravenously, nasally via inhalation,intramuscularly, sublingually or orally. In some embodiments of thecalcitonin gene-related peptide (CGRP) receptor antagonist for use, theCGRP receptor antagonist is in a pharmaceutical vehicle formulated fortopical, dermal, intradermal, subcutaneous, dermal infusion,subcutaneous infusion, intraocular, buccal, intravenous, nasal,inhalation, intramuscular, sublingual or oral administration. In someembodiments of the calcitonin gene-related peptide (CGRP) receptorantagonist for use, the effective amount comprises an amount of about 50μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 200 μg, 300 μg, 400 μg, 500 μg,600 μg, 700 μg, 800 μg, 900 μg, 1 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg,100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mgor 1000 mg or any amount in between a range defined by any twoaforementioned values. In some embodiments of the calcitoningene-related peptide (CGRP) receptor antagonist for use, the calcitoningene-related peptide (CGRP) receptor antagonist is administered at leastfour times a day, three times a day, two times a day, or once a day. Insome embodiments of the calcitonin gene-related peptide (CGRP) receptorantagonist for use, the patient has diabetes. In some embodiments of thecalcitonin gene-related peptide (CGRP) receptor antagonist for use, thepatient has been identified or selected to receive a drug for glaucoma.In some embodiments of the calcitonin gene-related peptide (CGRP)receptor antagonist for use, the drug is associated with nerve orcentral nervous system damage or neuronal dysfunction. In someembodiments of the calcitonin gene-related peptide (CGRP) receptorantagonist for use, the drug is a beta blocker. In some embodiments ofthe calcitonin gene-related peptide (CGRP) receptor antagonist for use,the CGRP receptor antagonist is administered within a pharmaceuticallyacceptable formulation. In some embodiments of the calcitoningene-related peptide (CGRP) receptor antagonist for use, the drug isintroduced, provided or administered to said patient before, during orafter administering the CGRP receptor antagonist. In some embodiments ofthe calcitonin gene-related peptide (CGRP) receptor antagonist for use,the CGRP receptor antagonist is used in combination with the drug.

In an eleventh aspect, an effective amount of calcitonin gene-relatedpeptide (CGRP) receptor antagonist or pharmaceutically acceptable saltthereof for use in reducing LDL in a patient in need thereof, isprovided. In some embodiments of the calcitonin gene-related peptide(CGRP) receptor antagonist for use, the CGRP receptor antagonist is apeptide or pharmaceutically acceptable salt thereof comprising astructure of Formula I:

X1-Y1-Z1   (I)

wherein:

X1 is a modified N-terminal fragment (i.e., region) of calcitoningene-related peptide comprising from five to seven amino acid residues,wherein only two amino acid residues of the N-terminal fragment arecysteine (Cys), wherein the residue at the C-terminal end of the regionis Cys, and wherein the residue immediately preceding the C-terminal Cysresidue of the region is a non-threonine substitution of the threonine(Thr) residue of position 6 of human GCRP;

Y1 is a central core region wherein at least one amino acid of thecentral core is arginine (Arg) or lysine (Lys) and the central corecomprises an α-helix; and

Z1 is a modified C-terminal fragment (i.e., region) of calcitoningene-related peptide comprising from five to seven amino acid residueswith a C-terminal amide, where at least one amino acid of the C-terminalfragment is phenylalanine (Phe), tyrosine (Tyr), proline (Pro) orhydroxyproline (Hyp). In some embodiments of the calcitonin gene-relatedpeptide (CGRP) receptor antagonist for use, the CGRP receptor antagonistcomprises a sequence set forth in one of SEQ ID NO: 1(NH2-Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 2(NH2-Ala-Cys-Asp-Thr-Ala-Ser-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 3(NH2-Ala-Cys-Asp-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 4(NH2-Ala-Cys-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 5(NH2-Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 6(NH2-Ala-Cys-Arg-Phe-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 7(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 8(NH2-Cys-Ser-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 9(NH2-Ala-Cys-Asp-Thr-Ala-Leu-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 10(NH2-Ala-Cys-Asp-Thr-Ala-Ile-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 11(NH2-Ala-Cys-Asn-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 12(NH2-Cys-Ser-Asn-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 13(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2),SEQ ID NO: 14(Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Val-Asp-Pro-Ser-Ser-Pro-His-Ser-Tyr-NH2),SEQ ID NO: 15(Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Thr-His-Arg-Leu-Ala-Gly-Leu-Leu-Ser-Arg-Ser-Gly-Gly-Val-Val-Lys-Asn-Asn-Phe-Val-Pro-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 57(NH2-Ala-Cys-Asp-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or SEQ ID NO: 58(NH2-Ala-Cys-Asp-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or a pharmaceutically acceptable salt thereof. In some embodiments ofthe calcitonin gene-related peptide (CGRP) receptor antagonist for use,the CGRP antagonist comprises a sequence selected from the groupconsisting of the sequences set forth in SEQ ID NO: 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12 and 13. In some embodiments of the calcitoningene-related peptide (CGRP) receptor antagonist for use, the patient issuffering from high LDL concentration in the blood. In some embodimentsof the calcitonin gene-related peptide (CGRP) receptor antagonist foruse, a level or amount of LDL in said patient is monitored or measuredbefore, during, or after administration of the effective amount of CGRPreceptor antagonist. In some embodiments of the calcitonin gene-relatedpeptide (CGRP) receptor antagonist for use, the patient is a male. Insome embodiments of the calcitonin gene-related peptide (CGRP) receptorantagonist for use, the patient has familial hypercholesterolemia. Insome embodiments of the calcitonin gene-related peptide (CGRP) receptorantagonist for use, the CGRP receptor antagonist is in a pharmaceuticalvehicle formulated for topical, dermal, intradermal, subcutaneous,dermal infusion, subcutaneous infusion, intraocular, buccal,intravenous, nasal, inhalation, intramuscular, sublingual or oraladministration. In some embodiments of the calcitonin gene-relatedpeptide (CGRP) receptor antagonist for use, the effective amountcomprises an amount of about 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg,200 μg, 300 μg, 400 μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg, 1 mg, 10mg, 20 mg, 30 mg, 40 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg,600 mg, 700 mg, 800 mg, 900 mg or 1000 mg or any amount in between arange defined by any two aforementioned values. In some embodiments ofthe calcitonin gene-related peptide (CGRP) receptor antagonist for use,the calcitonin gene-related peptide (CGRP) receptor antagonist isadministered at least four times a day, three times a day, two times aday, or once a day.

In a twelfth aspect, an effective calcitonin gene-related peptide (CGRP)receptor antagonist or a pharmaceutically acceptable salt thereof foruse in protecting a patient from nerve damage or nerve inflammation, isprovided. In some embodiments of the calcitonin gene-related peptide(CGRP) receptor antagonist for use, the patient suffers from a postischemic event. In some embodiments of the calcitonin gene-relatedpeptide (CGRP) receptor antagonist for use, the CGRP receptor antagonistis a peptide or a pharmaceutically acceptable salt thereof comprising astructure of Formula I:

X1-Y1-Z1   (I)

wherein:

X1 is a modified N-terminal fragment (i.e., region) of calcitoningene-related peptide comprising from five to seven amino acid residues,wherein only two amino acid residues of the N-terminal fragment arecysteine (Cys), wherein the residue at the C-terminal end of the regionis Cys, and wherein the residue immediately preceding the C-terminal Cysresidue of the region is a non-threonine substitution of the threonine(Thr) residue of position 6 of human CGRP;

Y1 is a central core region wherein at least one amino acid of thecentral core is arginine (Arg) or lysine (Lys) and the central corecomprises an α-helix; and

Z1 is a modified C-terminal fragment (i.e., region) of calcitoningene-related peptide comprising from five to seven amino acid residueswith a C-terminal amide, where at least one amino acid of the Z1 regionis phenylalanine (Phe), tyrosine (Tyr), proline (Pro) or hydroxyproline(Hyp). In some embodiments of the calcitonin gene-related peptide (CGRP)receptor antagonist for use, the CGRP receptor antagonist comprises asequence set forth in one of SEQ ID NO: 1(NH2-Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 2(NH2-Ala-Cys-Asp-Thr-Ala-Ser-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 3(NH2-Ala-Cys-Asp-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 4(NH2-Ala-Cys-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 5(NH2-Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 6(NH2-Ala-Cys-Arg-Phe-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 7(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 8(NH2-Cys-Ser-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 9(NH2-Ala-Cys-Asp-Thr-Ala-Leu-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 10(NH2-Ala-Cys-Asp-Thr-Ala-Ile-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 11(NH2-Ala-Cys-Asn-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 12(NH2-Cys-Ser-Asn-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 13(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2),SEQ ID NO: 14(Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Val-Asp-Pro-Ser-Ser-Pro-His-Ser-Tyr-NH2),SEQ ID NO: 15(Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Thr-His-Arg-Leu-Ala-Gly-Leu-Leu-Ser-Arg-Ser-Gly-Gly-Val-Val-Lys-Asn-Asn-Phe-Val-Pro-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 57(NH2-Ala-Cys-Asp-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or SEQ ID NO: 58(NH2-Ala-Cys-Asp-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or a pharmaceutically acceptable salt thereof. In some embodiments ofthe calcitonin gene-related peptide (CGRP) receptor antagonist for use,the CGRP antagonist comprises a sequence selected from the groupconsisting of the sequences set forth in SEQ ID NO: 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12 and 13. In some embodiments of the calcitoningene-related peptide (CGRP) receptor antagonist for use, the CGRPreceptor antagonist is in a pharmaceutical vehicle formulated fortopical, dermal, intradermal, subcutaneous, dermal infusion,subcutaneous infusion, intraocular, buccal, intravenous, nasal,inhalation, intramuscular, sublingual or oral administration. In someembodiments of the calcitonin gene-related peptide (CGRP) receptorantagonist for use, the calcitonin gene-related peptide (CGRP) receptorantagonist is administered at least four times a day, three times a day,two times a day, or once a day. In some embodiments of the calcitoningene-related peptide (CGRP) receptor antagonist for use, the effectiveamount comprises an amount of about 50 μg, 60 μg, 70 μg, 80 μg, 90 μg,100 μg, 200 μg, 300 μg, 400 μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg,1 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg,500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg or any amount inbetween a range defined by any two aforementioned values.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an example of a spontaneously active C-nociceptor beforeand after CGRP antagonist (SEQ ID NO: 1;NH2-ACDTAACVLGRLSQELHRLQTYPRTNVGSKAF-NH2) administration. Top panel:individual sweep of the recorded electrical activity in response tostimulation of the receptive field. Bottom panel: latency raster plotshowing the profile of a spontaneous C nociceptor. The arrow indicatesmoment of administration of the CGRP antagonist compound.

FIGS. 2A and 2B show an analysis of the spontaneous activity before andafter the CGRP receptor antagonist administration. FIGS. 2A and 2B:Comparison of two measures of spontaneous activity, SLI/10 min (FIG. 2A)and TI (%) (FIG. 2B) obtained 10 min before and 10 min after the CGRPreceptor antagonist administration. No significant differences wereobserved (paired t-test).

FIGS. 3A and 3B show an analysis of the spontaneous activity after theCGRP receptor antagonist administration. As shown is a comparison of twomeasurements of spontaneous activity, SLI/10 min (FIG. 3A) and TI (%)(FIG. 3B), obtained for each 10 minute bins throughout the 90 min afterthe drug administration.

FIGS. 4A and 4B show the measurement of the number of RGCs (Retinolganglion cells). FIG. 4A shows that the number of Brn3a positiveprofiles significantly decreased by 20.3% in the lasered eyes from thevehicle group as compared to contralateral control eyes (paired samplet-test, P=0.042). FIG. 4B shows that the number of Brn3a positive cellsincreased by 3.0% (P=0.43) in the CGRP antagonist group (SEQ ID NO: 1;NH2-ACDTAACVLGRLSQELHRLQTYPRTNVGSKAF-NH2).

FIGS. 5A and 5B show the experimental data for experiments in which thetotal number of optic nerve axons were accessed. FIG. 5A (control) and5B CGRP receptor antagonist (SEQ ID NO: 1;NH2-ACDTAACVLGRLSQELHRLQTYPRTNVGSKAF-NH2)) show that the total number ofoptic nerve axons did not differ significantly between lasered andcontralateral control eyes in any of the treatment groups, although thevehicle treatment group showed the highest decrease in the total numberof axons amongst all treatment groups and the CGRP antagonist (SEQ IDNO: 1; NH2-ACDTAACVLGRLSQELHRLQTYPRTNVGSKAF-NH2) group showed thesmallest decrease in the total number of axons (paired sample t-test,P>0.05 in all groups).

DEFINITIONS

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention pertains.

“About” as used herein when referring to a measurable value is meant toencompass variations of 20% or 10%, more preferably ±5%, even morepreferably ±1%, and still more preferably ±0.1% from the specifiedvalue.

As used herein, “antagonist” refers to a biologically active ligandwhich binds to a complementary biologically active receptor and inhibitsthe physiological response of the receptor. By way of example, as usedherein, a “CGRP receptor antagonist” and “CGRP antagonist,” refers to aligand that binds to a CGRP receptor and inhibits the physiologicalresponse of that receptor.

As used herein, “agonist” refers to a biologically active ligand whichbinds to its complementary biologically active receptor and activatesthe latter either to cause a biological response in the receptor or toenhance preexisting biological activity of the receptor.

As used herein, “pharmaceutically acceptable salt” refers to thenon-toxic alkali metal, alkaline earth metal, and ammonium saltscommonly used in the pharmaceutical industry including the sodium,potassium, lithium, calcium, magnesium, barium, ammonium, and protaminezinc salts, which are prepared by methods well known in the art. Theterm also includes non-toxic acid addition salts, which are generallyprepared by reacting the modified calcitonin gene-related peptideantagonists disclosed herein with a suitable organic or inorganic acid.Representative salts include the hydrochloride, hydrobromide, sulfate,bisulfate, acetate, oxalate, valerate, oleate, laurate, borate,benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,succinate, tartrate, napsylate, and the like. Thus, the term refers tothose salts which retain the biological effectiveness and properties ofthe free bases and which are not biologically or otherwise undesirable,formed with inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid and the like, and organicacids such as acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, malic acid, malonic acid, succinic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,mandelic acid, menthanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. For a descriptionof pharmaceutically acceptable salts as prodrugs, see Bundgaard et al.,1985.

“Percent (%) amino acid sequence identity” with respect to the sequencesidentified herein is defined as the percentage of amino acid residues ina candidate sequence that are identical with the amino acid residues inthe reference sequence, after aligning the sequences and introducinggaps, if necessary, to achieve the maximum percent sequence identity,and not considering any conservative substitutions as part of thesequence identity. Alignment for purposes of determining percent aminoacid sequence identity can be achieved in various ways that are withinthe skill in the art, for instance, using publicly available computersoftware such as BLAST, BLAST-2, ALIGN, ALIGN-2 or Megalign (DNASTAR)software. Those skilled in the art can determine appropriate parametersfor measuring alignment, including any algorithms needed to achievemaximal alignment over the full-length of the sequences being compared.For example, % amino acid sequence identity values generated using theWU-BLAST-2 computer program [Altschul et al., Methods in Enzymology,266:460-480 (1996)] uses several search parameters, most of which areset to the default values. Those that are not set to default values(i.e., the adjustable parameters) are set with the following values:overlap span=1, overlap fraction=0.125, word threshold (T)=11 andscoring matrix=BLOSUM62. A % amino acid sequence identity value isdetermined by dividing (a) the number of matching identical amino acidresidues between the each or all of the polypeptide amino acid sequenceof the reference chimeric receptor sequence provided in Table 2 and thecomparison amino acid sequence of interest as determined by WU-BLAST-2by (b) the total number of amino acid residues of the polypeptide ofinterest. In some alternatives, the percent sequence identity of aminoacids or nucleic acids are determined by computer software.

As used herein, “spontaneous nerve activity” or “spontaneous activity ofnerves” refers to the neural oscillation or rhythmic or repetitiveneural activity in the nervous system. This oscillation can be generatedin many ways by individual neurons or by the interaction betweenneurons. These neural oscillations can play an important role inneurological disorders such as during seizure activity in epilepsy andin the tremors in patients suffering from Parkinson's disease, forexample. Epilepsy is a common chronic neurological disordercharacterized by seizures. A tremor, as described herein, can be aninvoluntary, somewhat rhythmic muscle contraction and relaxationinvolving to-and-fro movements of one or more body parts. Most commontremors can include tremors of the hands, arms, eyes, face, head, vocalcords, trunk, and legs. Spontaneous nerve activity can also occur inC-fibers after partial damage to a nerve. In some embodiments, a methodof reducing spontaneous activity in nerves in a patient following nerveinjury is provided. The method comprises administering to the patient aneffective amount of CGRP receptor antagonist. In some embodiments, theCGRP receptor antagonist is a peptide antagonist. In some embodimentsthe peptide antagonist comprises a sequence set forth in any of SEQ IDNOS: 1-15, 57 and 58. As described in an exemplary embodiment herein,the peptide antagonist comprising the sequence set forth in SEQ ID NO: 1was used in a rat model having pathological spontaneous activity inC-nociceptors and C nerve fibers.

As used herein, “neurodegenerative disease” is any disease of a group ofhereditary or sporadic conditions characterized by progressivedysfunction, degeneration and death of specific populations of neuronswhich are often synaptically interconnected. As used herein,“neurodegeneration” refers to the progressive loss of structure orfunction of neurons and can include the death of neurons.Neurodegeneration can be caused by neurodegenerative nerve disease,which can affect the body's activities such as balance, movement,talking, breathing, vision and heart function, for example. Examples forcauses of neurodegeneration can include but is not limited to genetics,predisposition to medical conditions, alcoholism, tumor stroke, toxins,chemicals and viruses. In some cases the cause is unknown. Degenerativenerve diseases, or neurodegenerative diseases can include Alzheimer'sdisease, Amyotrophic lateral sclerosis, Friedreich's ataxia,Huntington's disease, Lewy body disease, Parkinson's disease, Spinalmuscular atrophy, diabetic neuropathy and glaucoma, for example. In someembodiments provided herein, a method for treating, preventing orameliorating the effects of neurodegeneration is provided. In someembodiments, the cause of neurodegeneration can be from genetics,predisposition to medical conditions, alcoholism, tumor, stroke, toxins,chemicals and viruses.

As used herein, “neurovascular disorder” or “neuromuscular disease”encompasses many diseases and ailments that can impair the functioningof the muscles, either directly, being pathologies of the voluntarymuscle, or indirectly, being pathologies of nerves or neuromuscularjunctions. Without being limiting, neurovascular disorders can includemuscular weakness, rigidity, loss of muscular control, myoclonus(twitching, spasming), and myalgia (muscle pains).

As used herein, the term “neuritis” or “nerve injury” can include injuryto the peripheral nerves such as laceration, focal contusion,stretch/traction injury, compression, drug injection injury, drugs,chemotherapeutic, neurovascular disorder, electrical injury, brachialplexus injury, foot drop injury, injury to the peroneal nerve andsciatic nerve, meralgia parasthetic (injury to the lateral femoralcutaneous nerve and femoral nerve, spinal accessory nerve injury (injuryto the spinal accessory nerve and cranial nerve) and traumatic nerveinjury. In some embodiments described herein, a method is provided fortreating a patient suffering from a nerve injury. In some embodiments,the nerve injury is from a laceration, focal contusion, stretch/tractioninjury, compression, drug injection injury, electrical injury, brachialplexus injury, foot drop injury, injury to the peroneal nerve andsciatic nerve, Meralgia parasthetic (injury to the lateral femoralcutaneous nerve and femoral nerve or spinal accessory nerve injury(injury to the spinal accessory nerve and cranial nerve). Nerve injurycan also lead to neurodegeneration. Treatments for nerve injury andneurodegenerative diseases can include but is not limited to a cellcycle inhibitor, a neuroprotectant, a nootropic agent, anticonvulsantagent, anxiolytic drug, antipsychotic drug, an analgesic,vasoprotectant, anti-amyloidogenic, immunomodulatory, anti-inflammatory,anti-parkinsonian, immunosuppressant, vasodilatory agent,immunostimulant, vasoprotectant, metabolic modulator, antihypertensive,centrally-acting muscle relaxant, nootropica agent, apoptosis inhibitor,growth factor agonist, smooth muscle relaxantium, neurotrophic agent,metabolic activator, ionotropic glutamate receptor antagonist,antihypertensive agent, antihypercholesterolemic agent,anti-amyloidogenic agent, anxiolytic; imaging agent; BDZ agonist, ClassIV antiarrhythmic agent, TRH agonist and a cardioprotectant. Drugs forneuritis can include but is not limited to interferon beta-la,interferon beta-1b, Kenalog-40, triamcinolone or Clinacort. In someembodiments, neuritis can lead to spontaneous nerve activity.

The term “neuroprotection,” as used herein refers to the preservation ofneuronal structure and/or function. During a neurodegenerative insultthe relative preservation of neuronal integrity implies a reduction inthe rate of neuronal loss over time. As such developing methods toprevent further damage to the nerves have been explored. For example,increased levels of oxidative stress can be caused in part byneuroinflammation which can further lead to more damage by oxidativestress. Without being limiting, antioxidants such as acetylcysteine,cocin, fish oil, and resveratrol have been tested to investigate theirrole in neuroprotection. In some embodiments described herein, a methodof providing neuroprotection in a patient in need thereof is provided.The method comprises administering to the patient an effective amount ofCGRP receptor antagonist.

Some pharmaceuticals, such as chemotherapy drugs, can affect the cellsof the nervous system by neurotoxicity or by neuropathy. Chemotherapydrugs can affect or damage the central nervous system, the peripheralnervous system and part of the peripheral nervous system called thecranial nerves. In some embodiments, a method of treating a patientsuffering from nerve damage is provided. In some embodiments, nervedamage is caused by pharmaceuticals such as chemotherapeutics. In someembodiments, the chemotherapeutics comprises cis-platinum chemotherapyor 5-Fluorouracil (5-FU) chemotherapy. Cis-platinum chemotherapy caninclude, but is not limited to the use of cisplatin, cisplatinum,platamin, neoplatin, cismaplat or cis-diamminedichloridoplatinum(III).The use of these types of chemotherapeutics can cause neurotoxicity,including but not limited to visual perception and hearing disorders.

The term “C-Nociceptors” as used herein, are sensory nerve cells thatrespond to damaging or potentially damaging stimuli by sending signalsto the spinal cord and brain. This process is called nociception, andcan cause the perception of pain in sentient beings. Nociceptors aresensory neurons that are found in any area of the body that can sensenoxious stimuli either externally or internally. Without being limiting,they can be found in tissues such as skin (cutaneous nociceptors),cornea and mucosa, for example. Internal nociceptors are in a variety oforgans, such as the muscle, joint, bladder, gut and continuing along thedigestive tract. The cell bodies of these neurons are located in eitherthe dorsal root ganglia or the trigeminal ganglia. The trigeminalganglia are specialized nerves for the face, whereas the dorsal rootganglia associate with the rest of the body. In some embodimentsdescribed herein, a method of treating a nerve injury is provided,wherein the method comprises administering to the patient an effectiveamount of CGRP receptor antagonist. In some embodiments, the nerveinjury is at a C-nociceptor or in group C nerve fibers.

The term “Group C nerve fibers” as used herein, are one of three classesof nerve fibers in the central nervous system and peripheral nervoussystem. The C group fibers are unmyelinated and have a small diameterand low conduction velocity. They include Postganglionic fibers in theautonomic nervous system (ANS), and nerve fibers at the dorsal roots (IVfiber). These fibers carry sensory information. Damage or injury tothese nerve fibers causes neuropathic pain.

The term “electromyoneurography” (EMNG), as used herein, is a method totest the level of nerve activity. EMNG is the combined use ofelectromyography and electroneurography for the measurement ofperipheral nerve's conduction velocity upon stimulation alongsideelectrical recording of muscular activity. In some embodiments describedherein, a method of treating a nerve injury in a patient is provided,wherein the patient is administered an effective amount of a CGRPantagonist peptide. In some embodiments, the method further comprisesmonitoring or measuring a level of nerve activity function in saidpatient before, during or after administration of the effective amountof CGRP receptor antagonist. In some embodiments, the monitoring isperformed by electromyoneurography.

The term “nerve conduction velocity test” (NCV), as used herein is atest commonly used to evaluate the function, and the ability of theelectrical conduction of the motor and sensory nerves of the human body.Nerve conduction velocity (NCV) is a common measurement made during thistest. A nerve conduction velocity test measures how quickly electricalimpulses move along a nerve. In some embodiments described herein, amethod of treating a nerve injury in a patient is provided, wherein thepatient is administered an effective amount of a CGRP antagonistpeptide. In some embodiments, the method further comprises monitoring ormeasuring a level of nerve activity function in said patient before,during or after administration of the effective amount of CGRP receptorantagonist. In some embodiments, the monitoring is performed by nerveconduction velocity test.

The term “diabetes” as used herein, is a group of metabolic diseases inwhich there are high blood sugar levels over a prolonged period.“Diabetic neuropathy” as described herein refers to a type of nervedamage that can occur when one has diabetes. High blood sugar can injurenerve fibers throughout the patient's body, but diabetic neuropathiescan often damages nerves in the legs and feet, for example. In someembodiments, a method of treating a patient suffering from neuropathy isprovided, wherein the patient is administered an effective amount of aCGRP antagonist. In some embodiments, the neuropathy is diabeticneuropathy.

Diabetic neuropathy is a common serious complication of diabetes. Yetone can often prevent diabetic neuropathy or slow its progress withtight blood sugar control and a healthy lifestyle. Depending on theaffected nerves, symptoms of diabetic neuropathy can range from pain andnumbness in the patient's extremities to problems with the patient'sdigestive system, urinary tract, blood vessels and heart. For somepeople, these symptoms are mild; for others, diabetic neuropathy can bepainful, disabling and even fatal. In some cases, medication is requiredto control the pain stemming from diabetic neuropathy.

The term “glaucoma” as described herein, is a group of eye diseaseswhich result in damage to the optic nerve and vision loss. The riskfactors for glaucoma include but are not limited to increased pressurein the eye, a family history of the condition, migraines, high bloodpressure, diabetes and obesity. For eye pressures a value equal to orgreater than 21 mmHg or 2.8 kPa is often used with higher pressuresleading to a greater risk. Treatment for glaucoma can include but is notlimited to beta-blockers, carbonic anhydrase inhibitors, hyperosmotics,cholinergics, adrenergic agonists and prostaglandin analogs. However,some patients can have high eye pressure for years and never developdamage. However, optic nerve damage may occur with normal pressure,known as normal-tension glaucoma. In some embodiments, a method ofproviding neuroprotection to the optic nerve is provided, wherein themethod comprises administering to the patient an effective amount ofCGRP receptor antagonist. In some embodiments, the patient is sufferingfrom glaucoma. In some embodiments, the patient is suffering fromdiabetes.

Without being limiting, two examples of glaucoma include open-angle andangle closure glaucoma. Open-angle glaucoma is the most common form ofglaucoma and accounts for at least 90% of all glaucoma cases. Open-angleglaucoma is caused by the slow clogging of the drainage canals,resulting in increased eye pressure, has a wide and open angle betweenthe iris and cornea, develops slowly and is a lifelong condition havingsymptoms and damage that are not noticed. The term “open-angle” meansthat the angle where the iris meets the cornea has a wide and open anglebetween the iris and the cornea. It is the most common type of glaucoma,and affects about three million Americans.

Angle closure glaucoma is a less common form of glaucoma and is causedby blocked drainage canals, resulting in a sudden rise in intraocularpressure. In angle closure glaucoma, the iris is not as wide and open asit should be and has a closed or narrow angle between the iris andcornea. This type of glaucoma develops very quickly, has very noticeablesymptoms and damage and demands immediate medical attention. Withoutbeing limiting, other variants of open-angle and angle-closure glaucomacan include secondary glaucoma, pigmentary glaucoma, pseudoexfoliativeglaucoma, traumatic glaucoma, neurovascular glaucoma, iridocornealendothelial syndrome (ICE) and Uveitic glaucoma. Vision loss from anytype of glaucoma, once it has occurred is permanent.

The term “familial hypercholesterolemia” (FH), as used herein, is aninherited disorder that is characterized by high cholesterol levels,specifically elevated levels of low-density lipoprotein (LDL, or “badcholesterol”), in the blood and early cardiovascular disease. Sinceindividuals with FH have an underlying body biochemistry that isslightly different, their high cholesterol levels are less responsive tothe types of cholesterol control methods which are usually moreeffective in people without FH (such as dietary modification and statintablets). FH can lead to aggressive and premature cardiovasculardisease. Without being limiting, problems caused by FH can include heartattacks, strokes, and narrowing of our heart valves. For individualswith FH, although diet and lifestyle are important, they are not thecause of high levels of LDL. In some FH patients, genetic mutations makethe liver incapable of metabolizing (or removing) excess LDL. The resultis very high LDL levels which can lead to premature cardiovasculardisease (CVD).

In some embodiments, a method of lowering levels of LDL in a patientsuffering from FH is provided, wherein the method comprisesadministering to the patient an effective amount of CGRP receptorantagonist. In some embodiments, the patient has been identified orselected to receive a drug or therapy for controlling LDL levels. Insome embodiments, the therapy is administration for controlling LDLlevels comprises statins, selective cholesterol absorption inhibitors,resins, bile acid sequestrant, bile acid-binding drugs or lipid loweringtherapies. In some embodiments, the method further comprises monitoringor measuring the level or amount of LDL in said patient before, during,or after administration of the effective amount of CGRP receptorantagonist. In some embodiments, the patient is already receivingtherapy for lowering LDL levels. In some embodiments, the effectiveamount of CGRP receptor antagonist is administered with a drug forlowering LDL levels. In some embodiments, the patient is a male.

Heterozygous FH is normally treated with statins, bile acidsequestrants, or other lipid lowering agents that lower cholesterollevels. Homozygous FH often does not respond to pharmaceutical therapyand may require other treatments, including LDL apheresis (removal ofLDL in a method similar to dialysis) and occasionally livertransplantation. The American Heart Association categorizes the risk ofheart disease based on LDL levels. Less that 100 mg/dL is considered tobe optimal and up to about 129 mg/dL is considered to be near optimal.Borderline high LDL ranges from about 130 mg/dL to 159 mg/dL and about160 to about 189 mg/dL is considered high. Any amount above 190 mg/dL iscategorized as very high. As many people with FH have levels of LDL atborderline LDL ranges or higher, new methods are desperately needed tocontrol LDL levels in these individuals.

“Subject” or “Patient” as described herein, can refer to any organismupon which the embodiments may be used or administered, e.g., forexperimental, diagnostic, prophylactic, and/or therapeutic purposes.Without being limiting, subjects can include animals (e.g., mammals suchas mice, rats, rabbits, non-human primates, and humans; insects; worms;etc.). A patient can also be any subject that is registered oridentified for receiving the methods of treatment as described herein.

“Combination therapy” as described herein, refers to a situation inwhich two or more different pharmaceutical agents are administered inoverlapping regimens so that the subject is simultaneously exposed tothe two or more different pharmaceutical agents.

“Therapeutically effective amount,” as described herein, can refer to anamount of a therapeutic agent whose administration, when viewed in arelevant population, correlates with or is reasonably expected tocorrelate with achievement of a particular therapeutic effect, includingfor example, amelioration of disease or disorder or delay of progressionof disease or disorder. The therapeutic effect may be objective (i.e.,measurable by some test or marker) or subjective (i.e., subject gives anindication of or feels an effect). A therapeutically effective amount iscommonly administered in a dosing regimen that may comprise multipleunit doses. For any particular therapeutic peptide, a therapeuticallyeffective amount (and/or an appropriate unit dose within an effectivedosing regimen) may vary, for example, depending on route ofadministration, or combination with other pharmaceutical agents. Also,the specific therapeutically effective amount (and/or unit dose) for anyparticular patient may depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific pharmaceutical agent employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and/orrate of excretion or metabolism of the specific fusion protein employed;the duration of the treatment; and like factors as is well known in themedical arts.

“Prophylactically effective amount” as described herein, refers to anamount that can prevent, delay or reduce the severity of a particulardisease or disorder in a patient a risk.

“Herpesvirus” as described herein, belongs to the herpesvirus family,Herpesviridae that infect humans. Without being limiting, symptoms caninclude watery blisters in the skin or mucous membranes. Lesions healwith a scab characteristic of herpetic disease. Sometimes, the virusescause very mild or atypical symptoms during outbreaks. However, asneurotropic and neuroinvasive viruses, HSV-1 and -2 persist in the bodyby becoming latent and hiding from the immune system in the cell bodiesof neurons. Herpesviruses can invade the nerves and nervous system.Shingles is due to a reactivation of varicella zoster virus (VZV), aherpesvirus, within a person's body. Chickenpox is due to an initialinfection with VZV. Once chickenpox has resolved, the virus may remaininactive in nerve cells. People suffering from outbreaks of shingles maydevelop ongoing nerve pain which may last for months or years, acondition called postherpetic neuralgia. In some embodiments of themethod of treatment provided herein, a patient suffering from aherpesvirus, is administered a CGRP antagonist.

“Ischemic event,” or “ischemia” as defined herein, refers to inadequateblood supply to an organ or part of the body, and can include the heartmuscles, for example. Reduction of circulation can lead to sensitivenerve tissue and muscle tissues.

DETAILED DESCRIPTION

As described herein, antagonists of the calcitonin gene-related peptide(CGRP) receptor can be used to control specific biological responses. Inparticular, the peptide antagonists of the CGRP receptor are useful inthe treatment of neuritis, glaucoma and other neurodegenerative diseasesand useful to provide neuroprotection and/or control of high LDL.

CGRP Peptide Antagonist for Administration

In some embodiments of the methods of treatment, the methods compriseadministration of a peptide CGRP receptor antagonist, also referred toherein, variously, as a CGRP receptor peptide antagonist or CGRP peptideantagonist and/or CGRP antagonist. The peptide CGRP receptor antagonistcan have the structure of Formula I:

X¹—Y¹—Z¹   (I)

wherein:

X¹ is an N-terminal fragment (i.e., region) of a modified calcitoningene-related peptide comprising at least five to seven amino acidresidues, where two amino acid residues of the N-terminal fragment arecysteine (Cys), wherein the final residue (i.e. the C-terminal endresidue) is Cys, and wherein the residue immediately preceding the finalCys residue is a non-threonine substitution of a threonine (Thr)residue;

Y¹ is a central core region comprising 15 to more than 24, 15 to 24, 15to 22, 18-22, or 19-20 residues where at least some of the residues ofthe central core are capable of forming an α-helix under physiologicalconditions, wherein at least one amino acid of the central core isarginine (Arg) or lysine (Lys) and the central core comprises anα-helix; and

Z¹ is a modified C-terminal fragment (i.e., region) of modifiedcalcitonin gene-related peptide comprising from five to seven amino acidresidues with a C-terminal amide, where at least one amino acid residueof the C-terminal fragment is phenylalanine (Phe) tyrosine (Tyr),proline (Pro) or hydroxyproline (Hyp);

or pharmaceutically acceptable salt thereof.

In some embodiments, the CGRP antagonist for administration comprises anamino acid sequence having at least 60%, at least 70% or at least 80%sequence identity to the amino acid sequence of SEQ ID NOS: 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 57 or 58 wherein said peptideretains antagonist activity.

In some embodiments, the CGRP antagonist for administration comprises anamino acid sequence having at least 90% sequence identity to the aminoacid sequence of SEQ ID NOS: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 57 or 58 wherein said peptide retains antagonist activity.

In some embodiments of the methods of treatment described herein, the X¹region of Formula I, has the characteristics that a residue whichprecedes the C-terminal cysteine by four, five or six amino acidpositions is also a cysteine, such that the two aforementioned cysteinescan form a disulfide bond. Residues between the two Cys residuesinvolved in the disulfide bond are unconstrained in sequence except thatthe residue preceding the C-terminal Cys residue of the fragment mustnot be a Thr, as mentioned above, and that there may not be more thantwo cysteines in the C-terminal 7 residues of the X¹ fragment. Theaforementioned disulfide bond stabilizes the structure of X¹,facilitating both formation of the alpha-helix in Y¹, below, and bindingof X¹ to the transmembrane component of a CGRP receptor in competitionwith CGRP.

In some embodiments of the methods of treatment described herein, a CGRPpeptide antagonist is administrated. The antagonist as disclosed hereincomprises a central core Y¹ comprising 15 to 22 residues. In someembodiments the antagonist as disclosed herein comprises a central coreY¹ comprising more than 24, 15 to 24, 15 to 22, 18-22, or 19-20 residueswhere at least some of the residues of the central core are capable offorming an α-helix under physiological conditions. The fourth residuefrom the N-terminus of this central core is frequently a positivelycharged residue, either Arginine (Arg) or Lysine (Lys). The eighteenthresidue is frequently Arginine. The length of the central core isconstrained not by the number of residues per se but by the stericconsiderations that require X¹ and Z¹ to be positioned so that they mayinteract with a target receptor at the cell membrane surface and at anextracellular domain, respectively, in competition with CGRP.

Z¹ is a modified C-terminal fragment (i.e., region) of a modifiedcalcitonin gene-related peptide comprising from five to seven amino acidresidues or more, with a C-terminal amide, and wherein at least oneamino acid of the Z¹ region is phenylalanine (Phe), proline (Pro),tyrosine (Tyr), or hydroxyproline (Hyp). Like Y¹ above, Z¹ isconstrained not by its sequence but by a functional requirement. In thecase of Z¹ that requirement is that it interact with a target receptorat a site in its extracellular domain such that when the antagonistbinds the CGRP receptor, in competition with CGRP, X¹ is positioned tointeract with the receptor at the cell surface and Z¹ interacts with aRAMP portion of the receptor.

In some embodiments of the methods of treatment described herein, theCGRP peptide antagonist for administration comprises an amino acidsequence having at least 60%, at least 70% or at least 80% sequenceidentity to the amino acid sequence of SEQ ID NOS: 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 57 or 58, wherein said peptide retainsantagonist activity.

In some embodiments of the methods of treatment described herein, theCGRP peptide antagonist for administration comprises an amino acidsequence having at least 90% sequence identity to the amino acidsequence of SEQ ID NOS: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 57 or 58, wherein said peptide retains antagonist activity.

In some embodiments of the methods of treatment, the CGRP peptideantagonist for administration comprises a core region of 18-22 residues.

In some embodiments of the instant methods, the CGRP peptide antagonistfor administration comprises the structure of Formula I, wherein theN-terminal fragment (X¹) comprises:

X¹¹-X¹²-X¹³-X¹⁴-X¹⁵-X¹⁶-X¹⁷ (SEQ ID NO: 16), where:

X¹¹ can be selected from the group consisting of alanine (Ala), cysteine(Cys), glycine (Gly), isoleucine (Ile), leucine (Leu), methionine (Met),phenylalanine (Phe), proline (Pro), tryptophan (Trp), and valine (Val);

X¹² can be selected from the group consisting of cysteine (Cys), serine(Ser), and tyrosine (Tyr);

X¹³ can be selected from the group consisting of arginine (Arg),asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamic acid(Glu), glutamine (Gln), histidine (His), lysine (Lys), serine (Ser),threonine (Thr), tyrosine (Tyr), and valine (Val);

X¹⁴ can be selected from the group consisting of arginine (Arg),asparagine (Asn), aspartic acid (Asp), glutamic acid (Glu), glutamine(Gln), histidine (His), leucine (Leu), lysine (Lys), phenylalanine(Phe), serine (Ser), threonine (Thr), tyrosine (Tyr), and valine (Val);

X¹⁵ can be selected from the group consisting of alanine (Ala), glycine(Gly), isoleucine (Ile), leucine (Leu), methionine (Met), phenylalanine(Phe), serine (Ser), tryptophan (Typ), and valine (Val);

X¹⁶ can be selected from the group consisting of alanine (Ala), glycine(Gly), isoleucine (Ile), leucine (Leu), methionine (Met), phenylalanine(Phe), serine (Ser), tryptophan (Typ), and valine (Val); and

X¹⁷ is cysteine (Cys), and is capable of forming a disulfide bridge witha cysteine residue in X¹¹, X¹², or X¹³; and

with the further limitation that only two residues of X¹ (that is, X¹⁷and only one of X¹¹, X¹², and X¹³) are cysteine residues.

In some embodiments of the methods of treatment, the CGRP peptideantagonist in the methods of treatment comprises the structure ofFormula I, X¹¹ is selected from the group consisting of Ala, Cys, andGly. In some embodiments of the methods of treatment, the CGRP peptideantagonist comprising the structure of Formula I, X¹² is selected fromthe group consisting of Cys and Ser, with the caveat that only one ofX¹¹ and X¹² can be Cys. In some embodiments of the methods of treatment,the CGRP peptide antagonist comprising the structure of Formula I, X¹³is selected from the group consisting of Arg, Asn, Asp, and Val. In someembodiments of the methods of treatment, the CGRP peptide antagonistcomprising the structure of Formula I, X¹⁴ is selected from the groupconsisting of Leu, Phe, and Thr. In some embodiments of the methods oftreatment, the CGRP peptide antagonist comprising the structure ofFormula I, X¹¹ is selected from the group consisting of Ala, Gly, andSer. In some embodiments of the methods of treatment, the CGRP peptideantagonist comprising the structure of Formula I, X¹¹ is selected fromthe group consisting of Ala, Ile, Leu, Ser, and Val.

In some embodiments of the methods of treatment, the CGRP peptideantagonist for administration comprises the structure of Formula I,X¹¹-X¹²-X¹³-X¹⁴-X¹⁵-X¹⁶-X¹⁷ is selected from the group consisting ofNH2-Ala-Cys-Asp-Thr-Ala-Ala-Cys (SEQ ID NO: 17),NH2-Ala-Cys-Asp-Thr-Ala-Ser-Cys (SEQ ID NO: 18),NH2-Ala-Cys-Asp-Thr-Ala-Val-Cys (SEQ ID NO: 19),NH2-Ala-Cys-Asn-Thr-Ala-Ala-Cys (SEQ ID NO: 20),NH2-Ala-Cys-Val-Leu-Gly-Ala-Cys (SEQ ID NO: 21),NH2-Ala-Cys-Arg-Phe-Gly-Ala-Cys (SEQ ID NO: 22),NH2-Ala-Cys-Asp-Leu-Ser-Ala-Cys (SEQ ID NO: 23),NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys (SEQ ID NO: 24),NH2-Cys-Ser-Asn-Thr-Ala-Ala-Cys (SEQ ID NO: 25),NH2-Ala-Cys-Asp-Thr-Ala-Leu-Cys (SEQ ID NO: 26),NH2-Ala-Cys-Asp-Thr-Ala-Ile-Cys (SEQ ID NO: 27),NH2-Ala-Cys-Asp-Thr-Ala-Leu-Cys (SEQ ID NO: 28),NH2-Ala-Cys-Asp-Thr-Ala-Ile-Cys (SEQ ID NO: 29),NH2-Ala-Cys-Asp-Leu-Ser-Val-Cys (SEQ ID NO: 30),NH2-Ala-Cys-Asp-Leu-Ser-Val-Cys (SEQ ID NO: 31),NH2-Ala-Cys-Asn-Leu-Ser-Val-Cys (SEQ ID NO: 32), andNH2-Cys-Ser-Asn-Thr-Ala-Val-Cys (SEQ ID NO: 33).

In some embodiments of the methods of treatment, one or more additionalresidues are fused N-terminally to X¹¹, thereby generating a polypeptidewith an N-terminal extension of residues with respect to X¹¹. In someembodiments of the instant methods of treatment, this extension affectsthe stability of the antagonist after administration.

In some embodiments of the methods of treatment, the CGRP peptideantagonist for administration comprises the structure of Formula I,wherein the central core region (Y¹) comprises a central core fragmentof human or salmon calcitonin. In some embodiments of the methods oftreatment, the fragment of human or salmon calcitonin comprises 18 to 21amino acids. In some embodiments of the methods of treatment, thefragment of human or salmon calcitonin comprises 18 to 20 amino acids.In some embodiments of the methods of treatment, the CGRP peptideantagonist for administration comprises the structure of Formula I, Y¹comprises 19 to 20 amino acids. In some embodiments of the methods oftreatment, the CGRP peptide antagonist comprising the structure ofFormula I, Y¹ is-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-(SEQ ID NO: 34) or-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-(SEQ ID NO: 35). In some embodiments of the methods of treatment, theCGRP peptide antagonist for administration comprises the structure ofFormula I, Y¹ has 95% sequence identity with-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-(SEQ ID NO: 34) or-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-(SEQ ID NO: 35).

In some embodiments of the methods of treatment, the CGRP peptideantagonist for administration comprises the structure of Formula I, thecentral core comprises a fragment of a calcitonin from any of a range ofspecies. In some embodiments of the methods of treatment, Y¹ can have a60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% sequence identity with the Y¹of SEQ ID NO: 34(Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-).In some embodiments of the methods of treatment, the CGRP peptideantagonist comprising the structure of Formula I, Y¹ can be-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-(SEQ ID NO: 35) or-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-(SEQ ID NO: 36) or-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Phe-Pro-Arg-Thr-Asn-(SEQ ID NO: 37) or-Val-Leu-Gly-Lys-Leu-Ser-Gln-Asp-Ile-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-(SEQ ID NO: 38) or-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Met-Gln-Thr-Tyr-Pro-Arg-Thr-Asp-(SEQ ID NO: 39) or-Leu-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Thr-Arg-Thr-Asp-(SEQ ID NO: 40) or-Val-Leu-Gly-Lys-Leu-Ser-Gln-Asp-Leu-His-Lys-Leu-Gln-Thr-Phe-Pro-Arg-Thr-Asp-(SEQ ID NO: 41) or-Met-Leu-Gly-Lys-Leu-Ser-Gln-Asp-Leu-His-Lys-Leu-Gln-Thr-Phe-Pro-Arg-Thr-Asp-(SEQ ID NO: 42) or-Val-Leu-Gly-Lys-Leu-Ser-Gln-Asp-Ile-His-Lys-Leu-Gln-Thr-His-Pro-Arg-Thr-Asp-(SEQ ID NO: 43). In some embodiments of the methods of treatment, Y¹ canhave a 60% or greater sequence identity with any of the Y¹ of thesequences immediately above.

Some embodiments of the instant method of treatment provide Y¹polypeptides that have at least about 60% amino acid sequence identity,alternatively at least about 61% amino acid sequence identity,alternatively at least about 62% amino acid sequence identity,alternatively at least about 63% amino acid sequence identity,alternatively at least about 64% amino acid sequence identity,alternatively at least about 65% amino acid sequence identity,alternatively at least about 66% amino acid sequence identity,alternatively at least about 67% amino acid sequence identity,alternatively at least about 68% amino acid sequence identity,alternatively at least about 69% amino acid sequence identity,alternatively at least about 70% amino acid sequence identity,alternatively at least about 71% amino acid sequence identity,alternatively at least about 72% amino acid sequence identity,alternatively at least about 73% amino acid sequence identity,alternatively at least about 74% amino acid sequence identity,alternatively at least about 75% amino acid sequence identity,alternatively at least about 76% amino acid sequence identity,alternatively at least about 77% amino acid sequence identity,alternatively at least about 78% amino acid sequence identity,alternatively at least about 79% amino acid sequence identity,alternatively at least about 80% amino acid sequence identity,alternatively at least about 81% amino acid sequence identity,alternatively at least about 82% amino acid sequence identity,alternatively at least about 83% amino acid sequence identity,alternatively at least about 84% amino acid sequence identity,alternatively at least about 85% amino acid sequence identity,alternatively at least about 86% amino acid sequence identity,alternatively at least about 87% amino acid sequence identity,alternatively at least about 88% amino acid sequence identity,alternatively at least about 89% amino acid sequence identity,alternatively at least about 90% amino acid sequence identity,alternatively at least about 91% amino acid sequence identity,alternatively at least about 92% amino acid sequence identity,alternatively at least about 93% amino acid sequence identity,alternatively at least about 94% amino acid sequence identity,alternatively at least about 95% amino acid sequence identity,alternatively at least about 96% amino acid sequence identity,alternatively at least about 97% amino acid sequence identity,alternatively at least about 98% amino acid sequence identity andalternatively at least about 99% amino acid sequence identity to a Y¹polypeptide fragment listed above.

In some embodiments of the methods of treatment, the CGRP peptideantagonist for administration comprises the structure of Formula I,wherein Z¹ comprises Z¹¹-Z¹²—Z¹³—Z⁴-Z¹⁵—Z¹⁶ (SEQ ID NO: 45) where:

Z¹¹ is selected from the group consisting of Ala, Gly, Ile, Leu, Met,Phe, Pro, Trp, and Val;

Z¹² is selected from the group consisting of Ala, Gly, Ile, Leu, Met,Phe, Pro, Trp, and Val;

Z¹³ is selected from the group consisting of serine (Ser), and tyrosine(Tyr);

Z⁴ is selected from the group consisting of Arg, Asn, Asp, Glu, Gln,His, Lys, Ser, Thr, and Tyr;

Z¹⁵ is selected from the group consisting of Ala, Gly, Ile, Leu, Met,Phe, Pro, Trp, and Val; and

Z¹⁶ is selected from the group consisting of Ala, Gly, Ile, Leu, Met,Phe, Pro, Trp, and Val. In some embodiments, Z¹¹ is Val. In someembodiments, Z¹² is Gly. In some embodiments, Z¹³ is Ser. In someembodiments, Z⁴ is Lys. In some embodiments, Z¹¹ is Ala. In someembodiments, Z¹⁶ is Phe. In some embodiments, Z¹¹-Z¹²—Z¹³—Z¹⁴-Z¹⁵—Z¹⁶ is-Val-Gly-Ser-Lys-Ala-Phe such that the C-terminus of the polypeptide isa carboxy moiety (SEQ ID NO: 46), or -Val-Gly-Ser-Lys-Ala-Phe-NH2, suchthat the C-terminus of the polypeptide is a carboxamide moiety (SEQ IDNO: 47).

In some embodiments of the methods of treatment, the C-terminal residueof Z¹ is Phenylalanine, Tyrosine, Proline or Hydroxyproline. In someembodiments the C-terminal residue of Z¹ is Phenylalanine.

In some embodiments Z¹ comprises at least one Phe residue.

In some embodiments the C-terminus of Z¹ is modified so that it isbounded by an amidated carboxy (—C(═O)NH2) moiety.

In some embodiments of the methods of treatment, the CGRP peptideantagonist for administration comprises the structure of Formula I, X¹is selected from the group consisting ofNH2-Ala-Cys-Asp-Thr-Ala-Ala-Cys- (SEQ ID NO: 17),NH2-Ala-Cys-Asp-Thr-Ala-Ser-Cys- (SEQ ID NO: 18),NH2-Ala-Cys-Asp-Thr-Ala-Val-Cys- (SEQ ID NO: 19),NH2-Ala-Cys-Asn-Thr-Ala-Ala-Cys- (SEQ ID NO: 20),NH2-Ala-Cys-Val-Leu-Gly-Ala-Cys-, NH2-Ala-Cys-Arg-Phe-Gly-Ala-Cys- (SEQID NO: 21), NH2-Ala-Cys-Arg-Phe-Gly-Ala-Cys- (SEQ ID NO: 22),NH2-Ala-Cys-Asp-Leu-Ser-Ala-Cys- (SEQ ID NO: 23),NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys- (SEQ ID NO: 24),Cys-Ser-Asn-Thr-Ala-Ala-Cys- (SEQ ID NO: 25),NH2-Ala-Cys-Asp-Thr-Ala-Leu-Cys- (SEQ ID NO: 26),NH2-Ala-Cys-Asp-Thr-Ala-Ile-Cys- (SEQ ID NO: 27),NH2-Ala-Cys-Asp-Thr-Ala-Leu-Cys- (SEQ ID NO: 28),NH2-Ala-Cys-Asp-Thr-Ala-Ile-Cys- (SEQ ID NO: 29),NH2-Ala-Cys-Asp-Leu-Ser-Val-Cys- (SEQ ID NO: 30),NH2-Ala-Cys-Asp-Leu-Ser-Val-Cys- (SEQ ID NO: 31),NH2-Ala-Cys-Asn-Leu-Ser-Val-Cys (SEQ ID NO: 32), andNH2-Cys-Ser-Asn-Thr-Ala-Val-Cys- (SEQ ID NO: 33); Y¹ can be-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-(SEQ ID NO: 34) or-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-(SEQ ID NO: 35); and Z¹ can be -Val-Gly-Ser-Lys-Ala-Phe having acarboxy-terminus (SEQ ID NO: 46) or -Val-Gly-Ser-Lys-Ala-Phe-NH2 (SEQ IDNO: 47).

In some embodiments of the methods of treatment, the CGRP peptideantagonist for administration comprises the structure of Formula I, theantagonist comprises from 28 to 35 amino acid residues, from 31 to 37amino acid residues, from 31 to 33 amino acid residues or 32 amino acidresidues.

In some embodiments of the methods of treatment, the CGRP peptideantagonist for administration comprises the structure of Formula I, theantagonist comprises -Ala-Cys-Asp-Thr-Ala-X¹⁶-Cys- (SEQ ID NO: 49),wherein X¹⁶ is any amino acid residue other than Thr.

In some embodiments of the methods of treatment, the CGRP peptideantagonist for administration comprises the structure of Formula I, theantagonist comprises a first peptide fragment/region having seven aminoacid residues or less, wherein said first peptide fragment has asequence from modified calcitonin gene-related peptide. In someembodiments, the CGRP peptide antagonist comprising the structure ofFormula I, the antagonist comprises a second peptide fragment havingseven amino acid residues or less, wherein said first and second peptidefragments are non-contiguous and each independently have a sequencewhich may be modified from calcitonin gene-related peptide. In someembodiments, the CGRP peptide antagonist comprising the structure ofFormula I, the antagonist comprises a third peptide fragment having 20amino acid residues or less, wherein said third peptide fragment has asequence from salmon calcitonin. In some embodiments, the CGRP peptideantagonist comprising the structure of Formula I, the second peptidefragment and the third peptide fragment are contiguous.

In some embodiments of the methods of treatment, the CGRP peptideantagonist for administration comprises a structure ofNH2-Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2(SEQ ID NO: 1), or a pharmaceutical acceptable salt thereof. In someembodiments, the antagonist has a structure ofNH2-Ala-Cys-Asp-Thr-Ala-Ser-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2(SEQ ID NO: 2), or a pharmaceutical acceptable salt thereof. In someembodiments of the methods of treatment, the CGRP peptide antagonist foradministration comprises a structure ofNH2-Ala-Cys-Asp-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2(SEQ ID NO: 3), or a pharmaceutical acceptable salt thereof. In someembodiments of the methods of treatment, the CGRP peptide antagonist foradministration comprises a structure ofNH2-Ala-Cys-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2(SEQ ID NO: 4), or a pharmaceutical acceptable salt thereof. In someembodiments of the methods of treatment, the CGRP peptide antagonist foradministration comprises a structure ofNH2-Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2(SEQ ID NO: 5), or a pharmaceutical acceptable salt thereof. In someembodiments of the methods of treatment, the CGRP peptide antagonist foradministration comprises a structure ofNH2-Ala-Cys-Arg-Phe-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2(SEQ ID NO: 6), or a pharmaceutical acceptable salt thereof. In someembodiments of the methods of treatment, the CGRP peptide antagonist foradministration comprises a structure ofNH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2(SEQ ID NO: 7), or a pharmaceutical acceptable salt thereof. In someembodiments, the antagonist has a structure ofNH2-Cys-Ser-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2(SEQ ID NO: 8), or a pharmaceutical acceptable salt thereof. In someembodiments, the antagonist has a structure ofNH2-Ala-Cys-Asp-Thr-Ala-Leu-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2(SEQ ID NO: 9), or a pharmaceutical acceptable salt thereof. In someembodiments of the methods of treatment, the CGRP peptide antagonist foradministration comprises a structure ofNH2-Ala-Cys-Asp-Thr-Ala-Ile-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2(SEQ ID NO: 10), or a pharmaceutical acceptable salt thereof. In someembodiments of the methods of treatment, the CGRP peptide antagonist foradministration comprises a structure ofNH2-Ala-Cys-Asn-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2(SEQ ID NO: 11), or a pharmaceutical acceptable salt thereof. In someembodiments of the methods of treatment, the CGRP peptide antagonist foradministration comprises a structure ofNH2-Cys-Ser-Asn-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2(SEQ ID NO: 12), or a pharmaceutical acceptable salt thereof. In someembodiments of the methods of treatment, the CGRP peptide antagonist foradministration comprises a structure of orNH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2(SEQ ID NO: 13), or a pharmaceutical acceptable salt thereof. In someembodiments, the antagonist has a structure ofAla-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Val-Asp-Pro-Ser-Ser-Pro-His-Ser-Tyr-NH2(SEQ ID NO: 14), or a pharmaceutical acceptable salt thereof. In someembodiments of the methods of treatment, the CGRP peptide antagonist foradministration comprises a structure ofAla-Cys-Asp-Thr-Ala-Ala-Cys-Val-Thr-His-Arg-Leu-Ala-Gly-Leu-Leu-Ser-Arg-Ser-Gly-Gly-Val-Val-Lys-Asn-Asn-Phe-Val-Pro-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2(SEQ ID NO: 15), or a pharmaceutical acceptable salt thereof. In someembodiments of the methods of treatment, the CGRP peptide antagonist foradministration comprises a structure ofNH2-Ala-Cys-Asp-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2(SEQ ID NO: 57) or a pharmaceutical acceptable salt thereof. In someembodiments of the methods of treatment, the CGRP peptide antagonist foradministration comprises a structure ofNH2-Ala-Cys-Asp-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2(SEQ ID NO: 58), or a pharmaceutically acceptable salt thereof. The CGRPpeptide antagonist of the present disclosure can also be administeredwithin a pharmaceutical composition comprising one of the compoundsabove. The pharmaceutical composition can be used in a method of any oneof the embodiments provided herein, the method comprising administeringto an individual an effective amount of a CGRP peptide antagonist.

In some embodiments of the methods of treatment, the CGRP peptideantagonist for administration comprises the structure of Formula I,wherein Y¹ includes-Ala-Glu-Ala-Ala-Ala-Lys-Glu-Ala-Ala-Ala-Lys-Glu-Ala-Ala-Ala-Lys-Ala-(SEQ ID NO: 50),-Ala-Lys-Ala-Ala-Ala-Glu-Lys-Ala-Ala-Ala-Glu-Lys-Ala-Ala-Ala-Glu-Ala-(SEQ ID NO: 51),-Ala-Glu-Ala-Ala-Lys-Ala-Glu-Ala-Ala-Lys-Ala-Glu-Ala-Ala-Lys-Ala- (SEQID NO: 52), or-Ala-Lys-Ala-Ala-Glu-Ala-Lys-Ala-Ala-Glu-Ala-Lys-Ala-Ala-Glu-Ala- (SEQID NO: 53).

In some embodiments of the methods of treatment, the CGRP antagonistcomprises a sequence selected from the group consisting of the sequencesset forth in SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13.

In some embodiments of the methods of treatment, the CGRP peptideantagonist for administration comprises an amino acid sequence having atleast 60% sequence identity to the amino acid sequence of SEQ ID NOS: 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 57 or 58, wherein saidpeptide retains antagonist activity. In some embodiments of the methodsof treatment, the CGRP peptide antagonist for administration comprisesan amino acid sequence having at least 70% sequence identity to theamino acid sequence of SEQ ID NOS: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 57 or 58, wherein said peptide retains antagonistactivity. In some embodiments of the methods of treatment, the CGRPpeptide antagonist for administration comprises an amino acid sequencehaving at least 80% sequence identity to the amino acid sequence of SEQID NOS: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 57 or 58,wherein said peptide retains antagonist activity. In some embodiments,the amino acid sequence can have at least 90% sequence identity to theamino acid sequence of SEQ ID NOS: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 57 or 58, wherein said peptide retains antagonistactivity. In some embodiments, the amino acid sequence can have at least95% sequence identity to the amino acid sequence of SEQ ID NOS: 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 57 or 58, wherein said peptideretains antagonist activity. In some embodiments, the amino acidsequence can have at least 97% sequence identity to the amino acidsequence of SEQ ID NOS: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 57 or 58, wherein said peptide retains antagonist activity.

Doses of the Antagonist and Routes of Administration

In some embodiments of the methods of treatment, the CGRP peptideantagonist can be administered to a patient susceptible to or otherwiseat risk of a particular neurodegenerative disease and that is sufficientto prevent, delay or lessen the severity of such disease. Such an amountis defined to be a “prophylactically effective amount” or“prophylactically effective dose” and can also be referred to as a“therapeutically effective dose.” In this use, the precise amounts to beadministered depend, for example, on the patient's state of health andweight, and can be readily determined by one of ordinary skill in theart. In a preferred embodiment, the antagonist can be administered to apatient in need of neuroprotection.

Without being limiting, a patient in need of neuroprotection hassuffered from an assault likely to cause nerve damage such as, forexample, an ischemic event, a nerve injury from a drug or a disease, orintraocular pressure affecting the optic nerve.

Patients in need of neuroprotection can suffer from neurodegenerativediseases such as Parkinson's disease, progressive supranuclear palsy,corticobasal degeneration and multisystem atrophy.

In some embodiments of the methods of treatment, the CGRP antagonistscan be administered, in a therapeutically effective amount, to a patientsuffering from spontaneous nerve activity resulting, for example, inpain or discomfort and/or contributing to progressive nerve damage. Suchspontaneous nerve activity may be the result of acute of chronicstimulation or chronic dysfunction of nerves, especially theC-nociceptors. In some embodiments, the patient in need of reduction ofspontaneous nerve activity is suffering from a Herpesvirus. In someembodiments, the patient in need of reduction of spontaneous nerveactivity is suffering from shingles.

In some embodiments of the methods of treatment, the CGRP peptideantagonists can be administered to a patient suffering from high LDLlevels in a therapeutically effective amount, that is an amountsufficient to reduce said LDL levels. In this use, the precise amountsto be administered depend, for example, on the patient's state of healthand weight, and can be readily determined by one of ordinary skill inthe art.

The dosage ranges for the administration of an antagonist for theinstant methods described herein, are those sufficient to produce atherapeutic effect.

In some embodiments of the methods of treatment provided herein, theCGRP receptor peptide antagonists are provided in a pharmaceuticalcomposition comprising the CGRP receptor peptide antagonist and inactiveingredients such as a pharmaceutical carrier or diluent. The peptideantagonist containing a pharmaceutical composition can be administeredby any means, as known to those of skill in the art, and include,without limitation, oral, pulmonary, parenteral (intramuscular,intraperitoneal, intravenous, or subcutaneous injection), inhalational(via a fine powder formulation, or aerosol), transdermal, intranasal,intraocular, buccal or sublingual routes of administration and can beformulated in dosage forms appropriate for each route of administration.In some embodiments, the peptide antagonist containing pharmaceuticalcomposition is administered is administered topically, dermally,intradermally, subcutaneously, via dermal infusion, via subcutaneousinfusion, intraocularly, buccally, intravenously, nasally,intraocularly, via inhalation, intramuscularly, sublingually or orally.See, for example, Bernstein, et al. PCT Patent Publication No. WO93/25221, published Dec. 23, 1993; Pitt, et al. PCT Patent PublicationNo. WO 94/17784, published Aug. 18, 1994; and Pitt, et al. EuropeanPatent Application 613,683, published Sep. 7, 1994.

Although the exact dosage will be determined on anindication-by-indication basis, in most cases, some generalizationsregarding the dosage can be made. The daily dosage regimen for an adulthuman patient may be, for example, an intraocular, intravenous,intraperitoneal, subcutaneous, or intramuscular dose of the antagonistat an exemplary range of between 0.001 mg and 100 mg, or an exemplaryrange of between 0.005 mg and 5 mg. Those of skill in the art willappreciate that dosing for topical, transdermal, oral, pulmonary (viainhalation), intranasal, buccal, sublingual, or related non-parenteralroutes of administration may be higher for parenteral administration.Dosing in this case may be, for example, may be greater than 100 mg, forexample, may be 200 mg, 300 mg, 400 mg, 600 mg, 500 mg, 1000 mg, or anyamount in between any two of the aforementioned amounts. Additionally,the CGRP antagonist may be formulated with one or more ingredients thatfacilitate administration and/or uptake of the CGRP peptide. In cases ofadministration of a pharmaceutically acceptable salt, dosages may becalculated as the free base. In some embodiments of the methodsdescribed herein, the composition is administered at least once daily,once a week, twice a week or three times a week, or four times a week.In some embodiments of the method of treatment described herein, thecomposition is administered 1, 2, 3 or 4 times per day or as a singleacute dose. In some embodiments of the methods described herein, theCGRP antagonist may be administered as a slow release formulation, forexample, via depot injection or via infusion pump. For example, the CGRPantagonist may be formulated to allow for once-monthly dosing or for usein slow release micro pump devices that allow for once yearly dosing(ex. an implanted osmotic pump device for delivery)

Suitable routes of administration for the instant methods ofadministration are likewise known to those of skill in the art and mayinclude, for example and without limitation, oral, ocularly,transmucosal or topical; parenteral delivery, including intramuscular,subcutaneous, intravenous, intramedullary injections, intrathecal,intraperitoneal, intranasal, or intraocular injections, as well asneedle-free subcutaneous delivery. Alternatively, the antagonist can bepart of any embodiments of the compositions as described herein and maybe administered by continuous intravenous infusion, preferably at a doseof each active ingredient up to 1000 mg per day. Subjects suffering fromchronic nerve pain can benefit from a continuous intravenous infusion ora controlled injection, for example from an infusion pump. Subjectssuffering from glaucoma can benefit from ocular administration of thecomposition. In some embodiments of the methods described herein, thedose of the active ingredient is 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100μg, 200 μg, 300 μg, 400 μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg, 1mg, 5 mg, 10 mg, 40 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 50 mg,100 mg, 200 mg, 300 mg, 400 mg or 500 mg 1000 mg or 2000 mg or anyamount in between any two aforementioned values. In some embodiments,the aforementioned dosage is administered in a single dose. In someembodiments, the peptides will be administered for a period ofcontinuous therapy, for example for a week or more, or for months oryears.

Typically, the dose range of the composition administered to the patientcan be from about 0.000001 to about 10 mg/kg of the patient's bodyweight. In some embodiments of the methods described herein, the doserange of the composition administered to the patient can be from0.000001, 0.000010, 0.00010, 0.0010, 0.010, 0.10, 1, 5 or 10 mg/kg ofthe patient's body weight, or any amount in between any twoaforementioned values. The dosage may be a single one or a series of twoor more given in the course of one or more days, as is needed by thepatient. In instances where human dosages for compounds have beenestablished for at least some condition, the present embodiments willuse those same dosages, or dosages that are between about 0.1% and 500%,more preferably between about 25% and 250% of the established humandosage. In some embodiments of the methods described herein, the dosageis 0.1%, 1%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%,300%, 400% or 500% of the established human dosage or any amount inbetween any two aforementioned values. Where no human dosage isestablished, as will be the case for newly-discovered pharmaceuticalcompounds, a suitable human dosage can be inferred from ED₅₀ or ID₅₀values, or other appropriate values derived from in vitro or in vivostudies, as qualified by toxicity studies and efficacy studies inanimals.

Other dose ranges for the method of administering the peptide antagonistin any of the methods provided herein will be apparent to the skilledpractitioner based on data from initial dose-response curves and otherdata that can be obtained by routine methods. In cases of administrationof a pharmaceutically acceptable salt, dosages may be calculated as thefree base. In some embodiments, the peptide antagonist of any of themethods provided herein is administered 1 time, 2 times, 3 times or upto 4 times per day or as a single acute dose. In some embodiments, thepeptides will be administered for a period of continuous therapy, forexample for a week or more, or for months or years. Depending on theseverity of a disease, such as chronic nerve pain experienced by apatient, administering is performed at least once daily, once a week,twice a week or three times a week.

In some embodiments of the methods of treatment, the compounds areadministered in sustained or controlled release dosage forms, includingwithout limitation, depot injections, osmotic pumps, transdermal(including electrotransport) patches, and the like, for prolonged and/ortimed, pulsed administration at a predetermined rate

In some embodiments of the methods of treatment, a patient is sufferingfrom chronic nerve pain or a post ischemic event. Ischemic injury canoccur due to interruption of circulation and may result in nerve damage.In some embodiments, a patient suffering from chronic nerve pain or apost ischemic event can be administered the antagonist by continuousintravenous infusion. In some embodiments, the antagonist isadministered by an external infusion pump to allow a patient toself-deliver a controlled amount of antagonist as needed.

Any of the well-known techniques, carriers, and excipients may be usedas suitable and as understood in the art; e.g., in Remington'sPharmaceutical Sciences, above.

Dosage amount and interval may be adjusted individually to provideplasma levels of the active moiety which are sufficient to maintain themodulating effects, or minimal effective concentration (MEC). The MECwill vary for each compound but can be estimated from in vitro data.Dosages necessary to achieve the MEC will depend on individualcharacteristics and route of administration. However, HPLC assays orbioassays can be used to determine plasma concentrations.

Reducing Spontaneous Activity in Nerves Following Nerve Damage byAdministration of a CGRP Antagonist

In one aspect, a method of reducing spontaneous activity in nervesfollowing nerve injury in a patient in need is provided, the methodcomprising administering to the patient an effective amount of CGRPreceptor antagonist. The CGRP receptor antagonist can have the structureof Formula I as described in the embodiments above.

Dosages for the CGRP peptide antagonist for administration are describedabove. The CGRP peptide antagonist can be delivered alone or as apharmaceutically acceptable salt thereof.

In some embodiments, the CGRP peptide antagonist comprises a sequenceselected from the sequences set forth in SEQ ID NOS: 1-15, 57 or 58.

In some methods for reducing spontaneous activity in nerves, forexample, following nerve injury, the CGRP receptor antagonist of FormulaI (X¹Y¹Z¹) is administered topically, dermally, intradermally,subcutaneously, via dermal infusion, via subcutaneous infusion,intraocularly, buccally, intravenously, nasally, intraocularly, viainhalation, intramuscularly, sublingually or orally. In someembodiments, the administering is performed daily, once a week, twice aweek, or three times a week. In some embodiments, the administering isperformed four times a day, three times a day, twice a day or once aday.

In some embodiments, the nerve injury is from a drug, such as achemotherapeutic. In some embodiments, the nerve injury is from aneurovascular disorder or neurodegenerative disease. In someembodiments, the drug causing a nerve injury is a heart medication (i.e.almitrine), an anti-cancer drug, antibiotic (i.e. chlorampheticol,Cipro), anti-fungal, immunosuppressant drug (i.e. Cyclosporine), musclerelaxant (i.e. Hydrazaline), anti-seizure medications (i.e. Phenytoin),anti-viral, anti-HIV drug, anti-inflammatory, centrally-acting musclerelaxant, nootropica agent, apoptosis inhibitor, growth factor agonist,smooth muscle relaxantium, chloroquine, isoniazid, metronidazole,nitrofurantoin, thalidomide, etanercept, infliximab, leflunomide,dapsone, phenytoin, disulfiram, didanosine, stavudine, Kenalog-40,triamcinolone, Clinacort or antiparasitic. In some embodiments, thenerves are C-Nociceptors or Group C nerve fibers.

In some embodiments, nerve injury is from a virus. In some embodiments,the patient is suffering from a herpesvirus. In some embodiments, thepatient is suffering from shingles. In some embodiments, the CGRPreceptor antagonist is administered within a pharmaceutically acceptableformulation. In some embodiments, the CGRP peptide antagonist comprisesa sequence set forth in SEQ ID NO's: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, or 15. In some embodiments, the CGRP peptide antagonistcomprises a sequence set forth in SEQ ID NO: 1.

In some embodiments, the patient has been identified or selected toreceive a drug for neurodegenerative diseases or a virus.

Methods of Providing Neuroprotection by Administration of a CGRPReceptor Antagonist

In another aspect, a method of providing neuroprotection in a patient inneed thereof is provided. Neuroprotection refers to the preservation ofneuronal structure and function. During a neurodegenerative insult, therelative preservation of neuronal integrity implies a reduction in therate of neuronal loss over time. Neuroprotection is a widely exploredtreatment option for central nervous system (CNS) disorders. These CNSdisorders can include but are not limited to neurodegenerative diseases,stroke, traumatic brain injury, spinal cord injury, and acute managementof neurotoxin consumption (i.e. methamphetamine overdoses).Neuroprotection can be used to prevent or slow disease progression andsecondary injuries by halting or at least slowing the loss of neurons.Despite differences in symptoms or injuries associated with CNSdisorders, many of the mechanisms behind neurodegeneration are the same.Common mechanisms include increased levels in oxidative stress,mitochondrial dysfunction, excitotoxicity, inflammatory changes, ironaccumulation, and protein aggregation. Common neuroprotective treatmentsare glutamate antagonists and antioxidants, which aim to limitexcitotoxicity and oxidative stress respectively. It has been discoveredthat CGRP receptor antagonists likewise can be neuroprotective.

In some embodiments, a patient in need of neuroprotection has sufferedfrom a neurodegenerative disease such as glaucoma, or suffered from anacute event such as stroke or spinal cord injury.

In some embodiments, a method of providing neuroprotection in a patientin need thereof is provided. The method comprises administering to thepatient an effective amount of CGRP receptor antagonist. The CGRPreceptor antagonist can be a peptide antagonist having the structure ofFormula I, as described in the embodiments above.

Dosages for the CGRP peptide antagonist for administration are describedabove. The CGRP peptide antagonist can be delivered alone or as apharmaceutically acceptable salt thereof.

In some embodiments, the CGRP peptide antagonist comprises a sequenceset forth in one of SEQ ID NOS: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 57 or 58. In some embodiments, the CGRP peptide antagonistcomprises a sequence set forth in one of SEQ ID NOS: 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12 or 13.

In some embodiments of the instant methods of administration, the CGRPreceptor antagonist is administered parenterally, ocularly,intraocularly, buccally, sublingually, orally, topically, dermally,intradermally, subcutaneously, via dermal infusion, or via subcutaneousinfusion. In some embodiments, the administering is performed daily,once a week, twice a week or three times a week. In some embodiments,the administering is performed four times a day, three times a day,twice a day, or once a day. In some embodiments, the CGRP receptorantagonist is formulated to allow for once a month or continuousadministration. In some embodiments, the method further comprisesmonitoring or measuring a level of nerve activity function in saidpatient before, during or after administration of the effective amountof CGRP receptor antagonist. In some embodiments, the patient issuffering from glaucoma, diabetes, Parkinson's disease, Alzheimer'sdisease, multiple sclerosis, diabetic neuropathy, cerebrovascularischemia, motor neuron disease, dementia, seizures, head injury or nervedamage. In some embodiments, the CGRP peptide antagonist comprises asequence set forth in SEQ ID NO's: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 57 or 58. In some embodiments, the CGRP peptideantagonist comprises a sequence set forth in one of SEQ ID NOS: 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12 or 13.

Methods of Treating Neuritis Neuropathy by Administration of a CGRPReceptor Antagonist

Neuritis is a general term for the inflammation of a nerve orinflammation of the peripheral nervous system. The causes for neuritiscan include but are not limited to physical injury, vascular injury,toxin aging, a genetic disorder, infection (viral or bacterial),diphtheria, herpes zoster (shingles), leprosy, Lyme disease, chemicalinjury such as chemotherapy, radiation therapy, alcoholism, autoimmunedisease, multiple sclerosis, Guillain-Barre syndrome, beriberi (vitaminB1 deficiency), cancer, Celiac disease, diabetes (Diabetic neuropathy),hypothyroidism, porphyria, vitamin B12 deficiency and vitamin B6 excess.Types of neuritis can include but are not limited to brachial neuritis,cranial neuritis such as Bell's palsy, optic neuritis, and vestibularneuritis.

In another aspect, a method of treating neuritis is provided. The methodcomprises administering to the patient an effective amount of CGRPreceptor antagonist or pharmaceutical salt thereof, as previouslydescribed.

The CGRP peptide antagonist can have the structure of Formula I, asdescribed above. The CGRP antagonist can comprise an amino acid sequencehaving at least 80% sequence identity to the amino acid sequence of SEQID NOS: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 15, 57 or 58wherein said peptide retains antagonist activity in these methods.

Dosages for the CGRP peptide antagonist for administration arepreviously described above. The CGRP peptide antagonist can be deliveredalone or as a pharmaceutically acceptable salt thereof as describedabove.

The CGRP receptor antagonist is administered as previously describedabove. In some embodiments, the method further comprises monitoring ormeasuring a level of nerve activity function in said patient before,during or after administration of the effective amount of CGRP receptorantagonist. In some embodiments, the neuritis is from a physical injury,vascular injury, toxin aging, a genetic disorder, infection (viral orbacterial), diphtheria, herpes zoster (shingles), leprosy, Lyme disease,chemical injury such as chemotherapy, radiation therapy, alcoholism,autoimmune disease, multiple sclerosis, Guillain-Barre syndrome,beriberi (vitamin B1 deficiency), cancer, Celiac disease, diabetes(Diabetic neuropathy), hypothyroidism, porphyria, vitamin B12 deficiencyand vitamin B6 excess. Types of neuritis can include but is not limitedto brachial neuritis, cranial neuritis such as Bell's palsy, opticneuritis or vestibular neuritis. In some embodiments the CGRP antagonistcomprises a sequence set forth in SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 57 or 58.

Methods of Treating Glaucoma in a Patient

In another aspect, a method of treating glaucoma in a patient isprovided. The method comprises administering to the patient in need aneffective amount of CGRP receptor antagonist, as described above. TheCGRP peptide antagonist can have the structure of Formula I, asdescribed above.

Dosages and routes of administration for the CGRP peptide antagonist areas described above.

In some embodiments, the patient has diabetes. In some embodiments, thepatient has been identified or selected to receive a drug for glaucoma.In some embodiments, the drug is a beta blocker, a prostaglandin, or analpha-adrenergic agonist. In some embodiments, the CGRP receptorantagonist is administered in addition to or in combination with anotherdrug such as a beta blocker, prostaglandin or α-adrenergic agonist. Insome embodiments, the CGRP antagonist comprises a sequence set forth inSEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 57 or 58.In some embodiments of the methods of treatment, the CGRP peptideantagonist is administered within a pharmaceutically acceptableformulation.

Methods of Reducing LDL Levels by Administration of a CGRP ReceptorAntagonist

Low-density lipoprotein (LDL) is one of the five major groups oflipoprotein. These groups, from least dense to most dense, arechylomicrons, very low-density lipoprotein (VLDL), intermediate-densitylipoprotein (IDL), low-density lipoprotein and high-density lipoprotein.The LDL particles can pose as a risk for cardiovascular disease whenthey invade the endothelium and become oxidized, since the oxidizedforms are more easily retained by the proteoglycans. Increasingconcentrations of LDL particles are strongly associated with increasingrates of accumulation of atherosclerosis within the walls of arteriesover time, eventually resulting in sudden plaque ruptures and triggeringclots within the artery opening, or a narrowing or closing of theopening, i.e. cardiovascular disease, stroke, and other vascular diseasecomplications.

Familial hypercholesterolemia (FH) is a diagnosis of individuals withvery significantly elevated low-density lipoprotein (LDL) cholesterol.FH is characterized by very high levels of LDL-C, as well as of totalcholesterol. The condition greatly increases the risk of hardening ofthe arteries (atherosclerosis), which can lead to heart attacks, strokesand other vascular conditions. Individuals with FH have a 20-foldincreased risk for coronary heart disease (CHD). Untreated men have a50% risk of a nonfatal or fatal coronary event by age 50 years;untreated women have a 30% risk by age 60 years.

Borderline high LDL ranges from about 130 mg/dL to 159 mg/dL and about160 to about 189 mg/dL is considered high. Any amount above 190 mg/dL iscategorized as very high. In some embodiments, the patient has an LDLlevel of 130 mg/dL, 140 mg/dL, 150 mg/dL, 160 mg/dL, 170 mg dL, 180mg/dL, 190 mg/dL, 200 mg/dL, or any concentration in between anyaforementioned values.

PCSK9 is responsible for only a small percentage of FH cases. The normalPCSK9 gene codes for an enzyme that breaks down the cholesterolreceptors after they have done their job. A mutation in this gene isunlike most mutations, which cause dysfunction of the affected gene. ThePCSK9 mutation increases the gene's function, leading to too fewremaining LDL receptors and thus an increase in the LDL cholesterollevel. As PCSK9 is responsible for only a small percentage of both FHcases and for high LDL levels, there is need to provide othertherapeutics to those suffering from high LDL levels.

In another aspect, a method of reducing LDL in a patient in need thereofis provided. The method comprises administering to the patient in needan effective amount of CGRP receptor antagonist, as described above. TheCGRP peptide antagonist can have the structure of Formula I, asdescribed above.

Dosages and routes of administration for the CGRP peptide antagonist aredescribed above.

In some embodiments, the patient is suffering from high LDLconcentration in the blood. In some embodiments, the patient has beenidentified or selected to receive a drug or therapy for controlling LDLlevels. In some embodiments, the method further comprises monitoring ormeasuring the level or amount of LDL in said patient before, during, orafter administration of the effective amount of CGRP receptorantagonist. In some embodiments, the therapy is administration forcontrolling LDL levels comprises statins, selective cholesterolabsorption inhibitors, resins, bile acid sequestrant, bile acid-bindingdrugs or lipid lowering therapies. In some embodiments, the patient isalready receiving therapy for lowering LDL levels. In some embodiments,the patient is a male. In some embodiments, the patient has familialhypercholesterolemia. In some embodiments the CGRP antagonist is apeptide comprising a sequence set forth in SEQ ID NO: 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 57 or 58. In some embodiments of themethods of treatment, the CGRP peptide antagonist for administration iswithin a pharmaceutically acceptable formulation.

In some embodiments, the patient has an LDL level over 200 mg/dL. Insome embodiments, the patient has an LDL level of 200 mg/dL, 220 mg/dL,240 mg/dL, 260 mg/dL, 280 mg/dL or 300 mg/dL or any concentration inbetween any two aforementioned values. In some embodiments, the patienthas an LDL level over 300 mg/dL.

ADDITIONAL EMBODIMENTS Embodiment 1 Assessment of the Effect of aPeptide CGRP Receptor Antagonist (SEQ ID NO: 1) on Spontaneous Activityin C-Nociceptors in a Rat Model of Nerve Injury.

To investigate the effects of a CGRP receptor antagonist on pathologicalspontaneous activity in C-nociceptors the following experiments wereperformed on Sprague-Dawly rats. Crush-inducing sciatic neuropathy wasproduced in 12 male Sprague-Dawley rats. Spontaneous activity in injuredC-nociceptors was then detected with microneurography and the responseto CGRP receptor antagonist was assessed under unblind conditions. Thisstudy aimed to assess the effect of the CGRP receptor antagonist, onelectrophysiological measures of spontaneous activity in subpopulationsof injured C-nociceptors in a model of neuropathic pain, and toinvestigate the effects of the CGRP receptor antagonist on pathologicalspontaneous activity in peripheral C-nociceptors.

Material and Methods

All experiments were performed following government recommendations forthe care and use of laboratory animals and were approved by theappropriate institutional committees for ethics in animal research.

As described herein, the experiment aimed to assess the effect of CGRPreceptor antagonists, such as the antagonist set forth in SEQ ID NO: 1,on electrophysiological measures of spontaneous activity insubpopulations of injured C-nociceptors in a model of neuropathic pain.

Animals for Testing Spontaneous Nerve Behavior.

Experiments were performed in one group of 12 adult male Sprague-Dawleyrats (Charles River, Laboratorios Espana, Barcelona, Spain) weighing312±12 g (mean±SD (standard deviation)) on the day of the nerve injury.Rats underwent a quarantine period of 72 hours before the start of theexperiments.

Animal Housing

Rats were housed in groups of three per cage. Cage cleaning wasperformed at least twice per week. Animals had rat food and tap water adlibitum. Animals were maintained under a standard light cycle (7:00a.m.-7:00 p.m.), in a temperature and humidity controlled environment.

Experimental Model of Crush-Induced Sciatic Neuropathy

All surgical procedures were performed under general anesthesia(ketamine 90 mg/kg+xylazine 10 mg/kg i.p. (intraperitoneal)). Thesciatic nerve was exposed at mid-thigh level. A standardized injury wasproduced by crushing the nerve three times in succession with a veryfine point forcep at a constant point, 90 mm from the tip of the thirddigit. The wound was then sutured by layers and disinfected withpovidone iodine. The animals received an analgesic subcutaneous (s.c).dose of buprenorphine and were maintained in a warm environment untilfull recovery from the anesthetic, and were allowed to recover from thenerve injury for a minimum of 70 days.

Administration of CGRP Receptor Antagonist

CGRP receptor antagonist (SEQ ID NO: 1) was dissolved according tomanufacturer's instructions in saline solution, at a final concentrationof 25 μg/Kg. Volumes of the intraperitoneal (i.p.) injected bolus rangedfrom 0.48 to 0.58 ml.

Microneurographic Recordings

Animals weighing 478±36 g (mean±SD) on the day of the recording wereanesthetized with ketamine (90 mg/Kg) and xylazine (10 mg/Kg) injectedi.p (intraperitoneal). Repeated administrations of one-half of theinitial dose were performed as required to maintain the level ofanesthesia, usually every hour.

The sciatic nerve was exposed at mid-thigh level, from the sciatic notchto the knee, and carefully freed from surrounding tissues. Animals wereplaced in prone position over a homeothermic Blanket (Harvard Apparatus,Holliston, Mass., USA). Skin temperature was monitored with an infraredtelethermometer pointing to the skin close to the receptive field of thenerve units under study. Upon completion of recording, rats wereeuthanized by an overdose of pentobarbital sodium injected i.p(Intraperitoneal).

Recordings of the sciatic nerve electrical activity were obtainedinserting a tungsten microelectrode (FHC, Bowdoinham, Me., USA, nominalimpedance 50-100KΩ, shaft Ø 175 μm (Ø=diameter)) into the sciatic nervetrunk with the aid of a micromanipulator. The recording electrode wascarefully advanced into the nerve with the micromanipulator untilcharacteristic neural audio signal could be heard. The method followsthe same principles of the microneurographic technique employed in humanpatients.

The neural signals were first amplified with an isolated, high inputimpedance amplifier, band-pass filtered (maximum range 50-5000 Hz) andpassed through a noise eliminator. The signal was then fed to an AM10audio-monitor with noise clipper (Grass Technologies, Warwick, R.I.,USA) and to computers running separate software for collectingspontaneous and electrically evoked activity. Electrical stimuli weredelivered to the cutaneous receptive field of the units by means of aconstant current stimulator (DS7A, Digitimer, Welwyn Garden City,Hertfordshire, UK).

Electrical stimuli were triggered and the responses to electricalstimulation recorded and analyzed with a PC and PCI-6221M dataacquisition board (National Instruments, Oklahoma City, Okla., USA)running QTRAC software (©Institute of Neurology, London, UK).Spontaneous activity was digitized at 20 kHz and recorded continuouslyon one of the computers running LabChart software (PowerLab Systems,ADInstruments Ltd., Bella Vista, New South Wales, Australia). Analysiswas performed with software written by Neuroscience Technologies,Science Park of Barcelona, Spain, to detect and quantify spontaneousactivity.

Trigger pulses were delivered to the stimulator at different frequenciesnecessary to induce ADS of conduction velocity of the recorded C-fibers.The digitized responses were stored on computer as raw data for off-lineanalysis. Digital filtering (band-pass 0.3-2 kHz) and clamping of thebaseline were performed both on-line and during off-line analysis for abetter visualization of action potentials.

Action potentials recorded in the sciatic nerve were displayed as araster plot of latencies. In the latency raster plots, each peak thatexceeds a specified level is represented by a dot on a plot with latencyas the ordinate and elapsed time as the abscissa. Depending on the levelchosen, the dots could represent action potentials or noise. The rasterplots presented herein display only selected units with adequatesignal-to-noise, and each dot represents an identified single unit.

An action potential propagated in an unmyelinated axon causeslong-lasting (up to a few minutes) activity-dependent slowing (ADS) ofconduction velocity. The ADS of the recorded C-fibers was assessed usinga modified protocol described by (Serra et al., 1999; incorporated byreference in its entirety herein). This consists of a sequence of 5steps: 1) 3 min baseline stimulation at 0.25 Hz; 2) 3 min pause (0 Hz);3) 3 min at 0.25 Hz; 4) 3 min 2 Hz train; and 5) return to 0.25 Hzbaseline until the latencies return to their original values. Thisstimulation method allows differentiation of profiles of ADS ofconduction velocity in individual C-fibers that correspond to specificfunctional types of peripheral nerve fibers:

Type 1: slow progressively (average latency increase of 28.3% at 2 Hz)and correspond to nociceptors. Nociceptors were subdivided into:

Type 1A: essentially unaffected by the stimulation pause, correspond tothe mechano-sensitive nociceptor.

Type 1B nociceptors show an appreciable reduction in latency at the endof the pause and correspond to the mechano-insensitive nociceptor.

Type 2: fibers slow to reach a plateau within 1 min of stimulation at 2Hz (average latency increase 5.2%) and are specific cold receptors.

Type 3: essentially unaffected by the stimulation at 2 Hz (slowing >3%);their function remains unclear (a recent report suggested that theyprobably represent the population of low-threshold mechano-sensitiveC-fibers).

Type 4: fibers slow to reach a plateau, partially recover conductionvelocity during the 2 Hz period, and correspond to efferent sympatheticfibers.

Only identified nociceptor units were examined in this study. Conductionvelocity was estimated by dividing the conduction distance by thebaseline latency at the stimulation rate of 0.25 Hz.

Some C-nociceptors in rat neuropathic pain models exhibit abnormalsudden shifts in baseline latency due to ongoing spontaneous activity.Correlation with raster plots has shown that bursts of spontaneousactivity are followed by transient ADS (activity dependent slowing)giving a ‘saw tooth’ appearance to the latency profile, identical tothat previously described in patients with neuropathic pain.

After the identification of C-fiber types, having assessed spontaneousactivity in at least one fiber and in order to test the effect of theCGRP receptor antagonist on C-nociceptors, the last step of the protocoldescribed above was extended as follows:

1. 60 min return to 0.25 Hz baseline

2. CGRP antagonist administration

3. 60-90 min of constant 0.25 Hz baseline stimulation to assess possibleeffects of the compound.

In the spontaneous C-nociceptors that were recorded, the followingmeasurements were made:

-   -   1. Significant Latency Increase (SLI): any departure from        baseline >300 μs (cut-off for latency fluctuations caused by        spontaneous activity). SLI were expressed as SLI/min. It is a        measure of how many times the unit has engaged in spontaneous        activity of at least 2 extra action potentials.    -   2. Total Increase (TI): Σ of % increase of all SLI in a given        unit of time. TI was expressed as TI/min, and it represents a        direct estimate of the total number of extra spikes that have        occurred per unit of time.

Baseline measurements were recorded during a 60 minute periodimmediately before drug administration. Post-treatment recording lastedfor 60-90 min. The analysis of the effect of treatment on spontaneousactivity was performed by comparing baseline activity (BT) with theeffect after treatment (AT) in 10 min bins, until the end of therecording (BT=baseline activity−before activity).

Statistical Analysis

Analysis of statistical differences was performed using the softwarepackage Prism 5.1 (GraphPad Software, Inc., La Jolla, Calif., USA). Pvalues of less than 0.05 were considered statistically significant. Thepaired Student t-test was used to compare the means of two matchedgroups.

Results Demographics of the Studied Population

A total of 12 rats were used in the present study. Table 1 details thenumber of animals, rat ID (identification code), body weight on the dayof the microneurography recording and days of maturation after inductionof the crush. All the rats received the treatment and all the recordingswere analyzed.

TABLE 1 Description of the 12 rats used in the investigation of theeffects of the CGRP receptor antagonist on pathological spontaneousactivity in peripheral C-nociceptors. weight maturation animal ID Ratcode micro days 1 C341 0-1 44 70 2 C342 0-0 43 72 3 C343 1-0 50 72 4C343 0-1 49 72 5 C344 0-0 50 73 6 C344 0-1 52 73 7 C344 1-0 44 76 8 C3450-1 47 76 9 C346 1-0 46 72 10 C346 0-0 50 72 11 C347 0-0 49 73 12 C3470-1 58 73

Number and Functional Subtypes of Recorded C-Fibers

From the 12 analyzed rats, a total of 42 C-fiber units were identified.As described in rats and humans, there was a predominance ofC-nociceptors and sympathetic fiber types. Measures ofactivity-dependent slowing were obtained from all fiber types, but onlyC-nociceptor types were further analyzed. Distribution of fibersubclasses and relative percentages are detailed in Table 2.

TABLE 2 Total number of C-fibers analyzed in the study, with relativedistribution of functional subclasses. Functional class N % totalNociceptor 35 83.33 Type 1A 6 14.29 Type 1B 27 64.29 Type 1 2 4.76 Type2 & 4 6 14.29 Type 3 1 2.38 TOTAL 42 100 Type 1A: Mechano-sensitiveC-nociceptor; Type 1B: Mechano-insensitive C-nociceptor; Type 1:undetermined class of C-nociceptor; Type 2: cold C-thermoreceptor; Type:3 unknown function; Type 4: sympathetic efferent.

There was a clear predominance of type 1B nociceptors over all the othertypes of fibers. There was an even distribution of recorded C-nociceptortypes among different animals, and there was no particular animal withan overrepresentation of spontaneous fibers.

Only spontaneous activity in C-nociceptors, which is always apathological phenomenon, was subsequently analyzed.

Spontaneous Activity in C-Nociceptors

Shown in FIG. 1 is a raster plot of a spontaneous C-fiber before andafter the CGRP receptor antagonist administration. From the 35nociceptors analyzed, 14 of them displayed spontaneous activity (33.33%from the total fibers), and all of them were of type 1B. Thisselectivity has recently been described in several neuropathic painconditions, both in humans and animals. As shown in FIG. 1 , the actionpotentials recorded in the sciatic nerve had virtually no excitationobserved after introduction of the CGRP receptor antagonist. Thus, CGRPantagonist (SEQ ID NO: 1), led to the surprising effect of preventingfurther spontaneous activity in the C-fibers.

The immediate effect of the CGRP receptor antagonist is shown in FIGS.2A and 2B. The analysis of SLI (Significant Latency Increase) and TI(Total Increase) did not reveal a statistically significant effect onthe spontaneous activity of C-nociceptors during the first 10 min afteradministration. The same analysis was done for the rest of the recordingand the results are shown in FIGS. 3A and 3B.

Morbidity and Mortality

All the rats studied were in good condition during the whole procedureand were sacrificed at the end of the experiment.

Conclusions

The peripheral neuropathy commonly induces spontaneous activity in type1B C-nociceptors, which is the substrate of the experience ofspontaneous burning and deep aching pain in patients with peripheralneuropathy.

As the CGRP peptide antagonist has only been used for vasodilationstudies, the function of CGRP peptide antagonist was investigated forits role in nerve function as CGRP receptors can also be located inneurons.

In this study there was less spontaneous activity at long intervalsafter the administration of a CGRP antagonist compound.

Embodiment 2: The Use of CGRP Antagonist in Rat Experimental GlaucomaModel

Ganglion cells of the retina and the optic nerve are the major sites ofdamage in glaucoma. The initial insult can be several possibilities suchas a gene mutation, increased intraocular pressure, or oxidative insult,in which all can lead to ganglion cell apoptosis, a natural but usuallyquiescent pathway that, when activated, leads to cell death. The sick,injured, or stressed cell essentially “commits suicide.” Visionresearchers have now worked out many of the steps in the apoptoticpathway in ganglion cells and can begin to test inhibitors that canblock the pathway and thus at least slow ganglion cell dysfunction anddeath.

A purpose of this study was to investigate neuroprotective properties ofCGRP antagonist in a rat experimental glaucoma model.

In this study, Wistar rats (n=12) were used for the experiments. Theneuroprotective properties of compounds were investigated in a rat lasermodel of glaucoma. Rats were divided into two groups of six rats each.One group served as a placebo control receiving vehicle (NaCl)injections, and the other was treated with a peptide CGRP receptorantagonist (SEQ ID NO: 1). For all 12 rats, the contralateral, untreatedeye served as a naïve undiseased control. The vehicle control and testcompound (20 mg/kg) were administered systemically (IP) daily for thewhole follow-up period of two weeks. The animals were sacrificed usingtranscardial perfusion. The retinal whole-mounts were thenimmuno-stained against retinal ganglion cell (RGC) marker Brn3a andastrocytic marker GFAP (glial fibrillary acidic protein). The number ofBrn3a positive profiles was manually counted from retinal images takenfrom central and peripheral parts of retina. The total number ofGFAP-immunoreactive cells (retinal astrocytes) was estimated usingstereology. The total number of RGC axons in the optic nerve wasestimated using stereology.

The results from the experiments show that the number of Brn3a positivecells decreased by approximately 20% in the vehicle treatment group, andincreased by approximately 3% in the CGRP antagonist treatment group ascompared to naïve eye. Similarly, the total number of optic nerve axonswas decreased by 18% in the vehicle group and increased by 1.7% in theCGRP antagonist treated group as compared to optic nerves fromcontralateral control eyes. There were no differences in the totalnumber of retinal astrocytes between the groups.

Conclusions: Although CGRP antagonists have been implicated in treatmentof migraines and in modulating CGRP-induced vasodilation, the systemicadministration of a CGRP antagonist in a rat glaucoma model surprisinglyshowed neuroprotection, an unrelated effect of vasodilation, at bothcellular and optic nerve axon levels. Additionally, treatment with aCGRP antagonist surprisingly showed an increase in the number of Brn3apositive cells in the retinal images, as well as an increase in thenumber of optic nerve axons, evidencing neurodegeneration.

Animals for the Glaucoma Study

All animals were treated in accordance with the ARVO Statement for theUse of Animals in Ophthalmic and Vision Research and the EC Directive86/609/EEC for animal experiments, using protocols approved andmonitored by the Animal Experiment Board of Finland (Experimentica Ltd.animal license number ESAVI/219/04.10.07/2014).

Rat Laser Model of Episcleral Vein Photocoagulation

The rat glaucoma model was induced unilaterally by laserphotocoagulation of episcleral veins as previously described (Kalesnykaset al., 2007). Anesthesia was performed using sodium pentobarbital (30mg/kg). The contralateral eye served as the control. Wistar rats (n=12)(Laboratory Animal Center, University of Eastern Finland, Kuopio,Finland) were used. The following efficacy measures were tested:

1. Quantification of Brn3a and GFAP-positive cells from retinal wholemounts manually and using stereology.

2. Quantification of optic nerve axons using stereology.

Treatment Administration

Following surgery to induce glaucoma, CGRP antagonist (SEQ ID NO: 1) (20μg/kg each) or vehicle control (NaCl) was administered intraperitoneally(IP), on a daily basis for two weeks following glaucoma inductionsurgery.

Animal Sacrifice and Tissue Collection

At the end of the study/follow-up period, the animals were sacrificed bytranscardial perfusion using 4% paraformaldehyde in 0.1M phosphatebuffer, pH 7.4. The brains, eyes and optic nerves were collected and theretinal whole mounts were prepared for immunohistochemical staining.

Morphological Assessment of Retinal Whole Mounts

Retinal whole mounts were immuno-stained against RGC (Brn3a) andastrocytic (GFAP) antibodies and the number of cells was quantifiedeither manually (Brn3a) or as previously described (Kalesnykas et al.,2008).

Morphological Assessment of Optic Nerve Axons

Semi-thin sections (1 μm-thick) of optic nerves were prepared and thetotal number of axons were estimated as previously described (Kalesnykaset al., 2012; Ragauskas et al., 2014).

Results Animals

The baseline weight of animals and the weight of animals prior thesacrifice in each treatment group are presented in Table 3.

TABLE 3 The weight of animals at the baseline and at the end of thestudy. Vehicle Control Group CGRP antagonist (NaCl) Baseline 538 ± 21603 ± 108 weight, g Weight prior to 524 ± 27 574 ± 93  sacrifice, g Dataare expressed as mean ± SD.

There was no significant difference in the weight between the groups(Mann-Whitney U test, P>0.05).

The Number of RGCs

The retinas were immuno-stained against RGC specific antibody Brn3a,retinas were imaged and Brn3a positive profiles were counted manuallyusing Image J software (NIH, Bethesda, Md., USA). Rat no. 4 (treatmentgroup with the CGRP antagonist) was excluded from the final analyses.

As shown in FIG. 4A, the number of Brn3a positive profiles significantlydecreased by 20.3% in the lasered eyes from the vehicle group ascompared to contralateral control eyes (paired sample t-test, P=0.042).

As shown in FIG. 4B, the number of Brn3a positive cells increased by3.0% (P=0.43) in the CGRP antagonist treated group.

The Total Number of Optic Nerve Axons

The total number of optic nerve axons were estimated from 1-μm-thicksections using StereoInvestigator software (MicroBrightfield Inc.,Williston, Vt., USA.

As shown in FIG. 5A, the total number of optic nerve axons was decreasedbetween lasered and contralateral control eyes in the vehicle treatmentgroup. In contrast, the CGRP antagonist group showed a slight increase(FIG. 5B) in the total number of axons as compared to contralateralcontrol eyes (paired sample t-test, P>0.05 in both groups).

Materials and Methods Processing, Staining and Stereology on Optic NerveAxons

After the optic nerves were post-fixed in 4% PFA (in 0.1M phosphatebuffer, pH 7.4) solution, they were placed in 1% osmium, dehydrated inascending alcohol concentration and placed in 1% uranyl acetate in 100%ethanol for 1 hour (Cone et al., 2012). Then the optic nerves wereembedded in epoxy resin mixture at 60° C. for 48 hours and semi-thinsections (1 μm-thick) of optic nerves were cut (Cone et al., 2012). Thetotal number of axons was estimated using optical fractionator method aspreviously described (Ragauskas et al., 2014). Briefly, axons werecounted manually using the Stereo Investigator software(MicroBrightField, VT, USA). First, the optic nerve section was outlinedusing CFI Plan Achro 4× objective (N.A. 0.1, W.D. 30). Thereafter, a CFIPlan Fluor 100× oil immersion objective (N.A. 1.30, W.D. 0.20) was usedfor axon counting.

Immunohistochemistry and Retinal Whole Mount Stereology

Retinal whole mounts were immuno-stained against RGC specific markerBrn3a (dilution 1:1,000; MAB1585, lot no. 2557607; Chemicon, Hayword,Calif., USA) and GFAP (1:1000; Dako, z0334, lot no. 20005461). Thefollowing secondary antibodies were used: goat anti-mouse Alexa Fluor488 (1:250, A11001, lot no. 1572559; Life Technologies, San Diego,Calif.) and goat anti-rabbit Alexa Fluor 594 (1:250 A11037, lot no.1588554; Life Technologies, San Diego, Calif.). DAPI (1:1,000, D9542,lot no. 034M4031V; Sigma, St. Louis Mo., USA) was used as counterstain.

Data Analysis

Quantitative data was graphed, analyzed and presented as mean±standarddeviation (SD) or standard error of mean (SEM). Parametric data wasanalyzed using paired-samples T-test (the contralateral eye of the sameanimal serves as control). Non-parametric data was analyzed usingMann-Whitney U test (comparison of 2 groups) or Wilcoxon paired-samplesT-test. For cell counts, assuming a Gaussian distribution of the data,any data point 2 standard deviations from the columnar mean wasexcluded. The differences are considered to be statistically significantat the P<0.05 level.

The results show that the number of Brn3a positive cells decreased byapproximately 20% in the vehicle treatment group, and increased byapproximately 3% in the CGRP antagonist treatment group as compared tonaïve eye. Similarly, the total number of optic nerve axons wasdecreased by 18% in the vehicle group, and increased by 1.7% in the CGRPantagonist treatment group as compared to optic nerves fromcontralateral control eyes. There were no differences in the totalnumber of retinal astrocytes between the groups.

Conclusion

Systemic administration of a peptide CGRP antagonist in a rat glaucomamodel unexpectedly showed neuroprotection both at cellular and opticnerve axon levels.

Embodiment 3. Assessment of the Effect of CGRP Receptor AntagonistAdministration on the Levels of LDL in Rats

Familial hypercholesterolemia (FH) is a genetic disorder that ischaracterized by high cholesterol levels, specifically very high levelsof low-density lipoprotein (LDL) in the blood, and early cardiovasculardisease. Individuals with FH can have high cholesterol levels that areless responsive to standard methods of treatment used to controlcholesterol levels. Without being limiting, these types of treatmentsinclude statins, selective cholesterol absorption inhibitors, resins(bile acid sequestrants or bile acid-binding drugs) and lipid-loweringtherapies. Nevertheless, treatment (including higher statin doses) andlifestyle changes are the standard of treatment employed for patientswith FH.

Study

In the course of a routine study of a peptide CGRP antagonist (SEQ IDNO: 1) to evaluate off-target effects of the compound, it was discoveredthat the test compound advantageously lowered LDL concentrations inblood.

Experimental Summary

Sprague Dawley rats were administered the CGRP antagonist daily via thesubcutaneous route for a period of 14 days, resulting in the surprisingeffect of LDL lowering. Fifty six animals (36 males and 20 females) weredistributed into four groups (consisting each of 5 males and 5 femalesper group and 4 extra males each for testing group as backups). Thegroups were as follows: G1—Control, G2—Low dose—100 mcg/kg,G3—Intermediate dose—300 mcg/kg, G4—High dose—1000 mcg/kg.

Rats from the treatment groups were dosed subcutaneously with CGRPreceptor antagonists (SEQ ID NO: 1) reconstituted with normal saline atdifferent dose levels per treatment group for 14 days. Control animalswere dosed with the vehicle alone.

There was no mortality or morbidity and no clinical signs were observedduring the entire study period except for four males from the high dosegroup that showed lethargy on day 10. Out of these four animals, threeanimals continued showing lethargy on day 11^(th) but all animalsnormalized from day 12.

The food consumption was normal for all the animals from all studygroups. Similarly no statistically significant difference was observedin body weight among the groups.

Experimental Procedures Test System Details/Characterization.

The species used for the studies were of the species Rattus norvegicus(Rat), and strain Sprague Dawley, from the Palamur Biosciences Pvt. Ltd.The weight variation at the time of dosing was about +20% of mean bodyweight of each sex. The age at the time of dosing was about 10-12 weeks.The male and female rats were nulliparous and non-pregnant. The numberof animals was 56 rats (36 male plus 20 females). 4 male rats were usedas extras for each group (total 16) for randomization and animalreplacement during acclimatization. Thus, the number of animals pergroup was 9 males and 5 females.

The acclimatization period was, at a minimum, 7 days. For therandomization, animals were selected and grouped based on stratifiedrandomization by using body weights one day before dosing (day 0) usingan Excel program. The route of administration of the antagonist was by asubcutaneous method. The frequency of the administration was daily forfourteen days. The dose volume was set at 5 ml/kg of body weight. Theduration of the treatment was fourteen days with administrationoccurring approximately at the same time each day.

The animals were housed at a temperature of 20.1 to 22.7° C. with arelative humidity of 49 to 59%. The animals were at a photo period orexposure of 12 hours of light and 12 hours of dark. The room airexchanges were at a minimum of 10-15 air exchanges per hour. For caging,the animals were housed in groups in poly propylene rat cages with paddyhusk bedding. The bedding material was changed daily. The animals wereidentified with cage cards and assigned animal identification numbers.The diet of the rats consisted of Amrut rodent feed and RO water, whichwas provided ad libitum.

Preparation and Administration of Test Item

While preparing the dose formulation, required quantities of test item(i.e. CGRP antagonist) was weighed separately. The required volume ofnormal saline was added to the test item. A clear solution was obtainedafter addition of normal saline to test item. The test item wasadministered subcutaneously at the desired dose level once daily for upto 14 days. Homogeneity of the test item in the vehicle was maintainedduring administration.

Observations

The following observations were recorded:

1. Clinical Signs

All animals were observed for any visible clinical signs includingchanges in fur, eyes, occurrence of secretions, excessive grooming,self-mutilation, lacrimation, piloerection, pupil size, changes in gait,posture and response to handling and convulsions.

2. Body weight

Body weight was recorded on day 1, 7, 11 and 15.

3. Feed consumption

Feed consumption was recorded daily and reported weekly.

4. Blood collection and Laboratory investigations

Blood samples for were collected from all animals on day 15. The animalswere fasted overnight before blood sampling but allowed access to waterad libitum for hematology and biochemistry. Blood samples were drawnfrom the retro-orbital plexus using a micro-hematocrit heparinized glasscapillary tube. Blood samples were centrifuged (3500 rpm) and aftercentrifugation plasma was separated for further analysis.

The following time windows for blood collection were not considered asdeviation: ±1 minute for 0.25 hour, ±2 minutes for 0.5 hour and ±5minutes for 1 to 8 hours and ±15 minutes for 24 hours.

Clinical Biochemistry

Total Cholesterol, Triglycerides, Low-density lipoprotein andHigh-density lipoprotein parameters are shown in Tables 4 and 5, formale and female rats, respectively. Data from the LDL analysis isshaded. Other non-cholesterol related parameters measured are not shown,but none were significantly different from control.

TABLE 4 Summary of Clinical biochemistry parameters at day 15 in malerats. T. Chol Trig HDL LDL GROUP/DOSE (mg/dL) (mg/dL) (U/L) (U/L) G1 -Control 78.40 69.00 50.40 14.20  ± ± ± ± 12.18 22.28  8.17 7.49 G2 - 100mcg/kg b.w. 78.00 121.40* 51.60 2.96 ± ± ± ± 20.95 43.48 13.81 1.16 G3 -300 mcg/kg b.w. 69.60 97.20 46.00 4.16 ± ± ± ± 10.55 22.79  6.89 0.85G4 - 1000 mcg/kg b.w. 58.20 82.40 37.00 4.72 ± ± ± ±  9.63 23.20  5.522.32 Data are expressed as Mean ± S.D.(n = 5). T. chol.—TotalCholesterol, Trig—Tryglycerides, LDL—Low-density lipoprotein,HDL—High-density lipoprotein.

TABLE 5 Summary of Clinical biochemistry parameters at day 15 in femalerats. T. Chol Trig HDL LDL GROUP/DOSE (mg/dL) (mg/dL) (U/L) (U/L) G1 -Control 69.80 61.60 49.20 8.28 ± ± ± ± 13.70 19.40  9.44 6.01 G2 - 100mcg/kg b.w. 84.20 70.60 59.00 11.08  ± ± ± ± 25.56 17.11 15.36 8.43 G3 -300 mcg/kg b.w. 91.00 84.00 61.60 12.60  ± ± ± ± 25.05 18.68 15.90 8.26G4 - 1000 mcg/kg b.w. 80.60 82.00 54.80 9.40 ± ± ± ± 15.40 28.48  9.345.78 Data are expressed as Mean ± S.D.(n = 5). T. chol.—TotalCholesterol, Trig—Tryglycerides, LDL—Low-density lipoprotein,HDL—High-density lipoprotein,

Lowering of LDL Levels in Rats

As shown, the administration of a CGRP receptor antagonist, led to thesurprising effect of decreasing LDL levels in rats. As shown in Tables 4and 5, the substantial LDL lowering can be seen especially in the malerats and at every test dose administered (100 to 1000 mc/kg b.w).

Conclusion

Systemic administration of a peptide CGRP antagonist surprisingly showeda metabolic effect, by lowering the LDL levels in normal rats.

With respect to the use of plural and/or singular terms herein, thosehaving skill in the art can translate from the plural to the singularand/or from the singular to the plural as is appropriate to the contextand/or application. The various singular/plural permutations may beexpressly set forth herein for sake of clarity.

It will be understood by those of skill within the art that, in general,terms used herein, and especially in the appended claims (e.g., bodiesof the appended claims) are generally intended as “open” terms (e.g.,the term “including” should be interpreted as “including but not limitedto,” the term “having” should be interpreted as “having at least,” theterm “includes” should be interpreted as “includes but is not limitedto,” etc.). It will be further understood by those within the art thatif a specific number of an introduced claim recitation is intended, suchan intent will be explicitly recited in the claim, and in the absence ofsuch recitation no such intent is present. For example, as an aid tounderstanding, the following appended claims may contain usage of theintroductory phrases “at least one” and “one or more” to introduce claimrecitations. However, the use of such phrases should not be construed toimply that the introduction of a claim recitation by the indefinitearticles “a” or “an” limits any particular claim containing suchintroduced claim recitation to embodiments containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (e.g., “a” and/or “an” should be interpreted to mean “at least one”or “one or more”); the same holds true for the use of definite articlesused to introduce claim recitations. In addition, even if a specificnumber of an introduced claim recitation is explicitly recited, thoseskilled in the art will recognize that such recitation should beinterpreted to mean at least the recited number (e.g., the barerecitation of “two recitations,” without other modifiers, means at leasttwo recitations, or two or more recitations). Furthermore, in thoseinstances where a convention analogous to “at least one of A, B, and C,etc.” is used, in general such a construction is intended in the senseone having skill in the art would understand the convention (e.g., “asystem having at least one of A, B, and C” would include but not belimited to systems that have A alone, B alone, C alone, A and Btogether, A and C together, B and C together, and/or A, B, and Ctogether, etc.). In those instances where a convention analogous to “atleast one of A, B, or C, etc.” is used, in general such a constructionis intended in the sense one having skill in the art would understandthe convention (e.g., “a system having at least one of A, B, or C” wouldinclude but not be limited to systems that have A alone, B alone, Calone, A and B together, A and C together, B and C together, and/or A,B, and C together, etc.). It will be further understood by those withinthe art that virtually any disjunctive word and/or phrase presenting twoor more alternative terms, whether in the description, claims, ordrawings, should be understood to contemplate the possibilities ofincluding one of the terms, either of the terms, or both terms. Forexample, the phrase “A or B” will be understood to include thepossibilities of “A” or “B” or “A and B.”

In addition, where features or aspects of the disclosure are describedin terms of Markush groups, those skilled in the art will recognize thatthe disclosure is also thereby described in terms of any individualmember or subgroup of members of the Markush group.

Any of the features of an embodiment of the first through twelfthaspects is applicable to all aspects and embodiments identified herein.Moreover, any of the features of an embodiment of the first throughtwelfth aspects is independently combinable, partly or wholly with otherembodiments described herein in any way, e.g., one, two, or three ormore embodiments may be combinable in whole or in part. Further, any ofthe features of an embodiment of the first through twelfth aspects maybe made optional to other aspects or embodiments.

REFERENCES

-   1. Ashina M, Bendtsen L, Jensen R, Schifter S, Olesen J. Evidence    for increased plasma levels of calcitonin gene-related peptide in    migraine outside of attacks. Pain. 2000 May; 86(1-2):133-8.-   2. Bundgaard, H. ed., 1985 Design of Prodrugs, Elsevier Science    Publishers, Amsterdam.-   3. Castel D, Sabbag I, Brenner O, Meilin S. Peripheral Neuritis    Trauma in Pigs: A Neuropathic Pain Model. J Pain. 2016 January;    17(1):36-49.-   4. Chader G J, Key needs and opportunities for treating glaucoma.    Invest Ophthalmol Vis Sci. 2012 May 4; 53(5):2456-60.-   5. Christopoulos G, Perry, K J, Morfis M, Tilakaratne, N, Gao Y,    Fraser N J, Main M J, Foord S M, and Sexton P M. Multiple Amylin    Receptors Arise from Receptor Activity-Modifying Protein Interaction    with the Calcitonin Receptor Gene Product. Mol Pharmacol. 1999 July;    56(1):235-42.-   6. Cone F E, Steinhart M R, Oglesby E N, Kalesnykas G, Pease M E,    Quigley H A (2012) The effects of anesthesia, mouse strain and age    on intraocular pressure and an improved murine model of experimental    glaucoma. Exp Eye Res. June; 99:27-35.-   7. Edvinsson L. 2001, CNS Drugs 15(10):745-53; Williamson, D. J.    2001 Microsc. Res. Tech. 53:167-178.-   8. Gallai V1, Sarchielli P, Floridi A, Franceschini M, Codini M,    Glioti G, Trequattrini A, Palumbo R. Vasoactive peptide levels in    the plasma of young migraine patients with and without aura assessed    both interictally and ictally. Cephalalgia. 1995 October;    15(5):384-90.-   9. Goadsby P J1, Edvinsson L, Ekman R. Vasoactive peptide release in    the extracerebral circulation of humans during migraine headache.    Ann Neurol. 1990 August; 28(2):183-7.-   10. Grant, A D, 2002, Brit. J Pharmacol. 135:356-362-   11. Gupta, N., and Yucel, Y. H., 2007, Glaucoma as a    neurodegenerative disease. Current Opin. Ophthalmol 18:110-114.-   12. Hay D L, Smith D M., Knockouts and transgenics confirm the    importance of adrenomedullin in the vasculature. Trends Pharmacol    Sci. 2001 February; 22(2):57-9.-   13. Kalesnykas G, Oglesby E N, Zack D J, Cone F E, Steinhart M R,    Tian J, Pease M E, Quigley H A (2012) Retinal ganglion cell    morphology after optic nerve crush and experimental glaucoma. Invest    Ophthalmol Vis Sci 53(7):3847-3857.-   14. Kalesnykas G, Uusitalo H (2007) Comparison of simultaneous    readings of intraocular pressure in rabbits using Perkins handheld,    Tono-Pen XL, and TonoVet tonometers. Greafes Arch Clin Exp    Ophthalmol 245: 761-762.-   15. Kalesnykas G, Tuulos T, Uusitalo H, Jolkkonen J (2008).    Neurodegeneration and cellular stress in the retina and optic nerve    in rat cerebral ischemia and hypo perfusion models. Neuroscience,    155(3):937-47.-   16. Lassen L H, Aderslev P A, Jacobsen V B, Iversen H K, Sperling B,    Olesen J. CGRP may play a causative role in migraine. Cephalalgia.    2002 February; 22(1):54-61.-   17. Marquest de Prado B, Russo A F. CGRP receptor antagonists: A new    frontier of anti-migraine medications Drug Discov Today Ther    Strateg. 2006 Winter; 3(4): 593-597.-   18. McLatchie L M, Fraser N J, Main M J, Wise A, Brown J, Thompson    N, Solari R, Lee G M and Foord S M. RAMPs regulate the transport and    ligand specificity of the calcitonin-receptor-like receptor. Nature    393, 333-339 (28 May 1998).-   19. Mimeault M1, Quirion R, Dumont Y, St-Pierre S, Fournier A.    Structure-activity study of hCGRP8-37, a calcitonin gene-related    peptide receptor antagonist. J Med Chem. 1992 Jun. 12;    35(12):2163-8.-   20. Miret J J, Rakhilina L, Silverman L and Oehlen B. Functional    Expression of Heteromeric Calcitonin Gene-related Peptide and    Adrenomedullin Receptors in Yeast. J Biol Chem. 2002 Mar. 1;    277(9):6881-7. Epub 2001 Dec. 3.-   21. Moskowitz M A, Neurogenic versus vascular mechanisms of    sumatriptan and ergot alkaloids in migraine. Trends Pharmacol Sci.    1992 August; 13(8):307-11.-   22. Mufson E J, Counts S E, Che S, Ginsberg S D. Neuronal gene    expression profiling: uncovering the molecular biology of    neurodegenerative disease. Progress in Brain ResearchVolume 158,    2006, Pages 197-222.-   23. Mulder H, Gebre-Medhin S, Betsholtz C, Sundler F, Ahren B. Islet    amyloid polypeptide (amylin)-deficient mice develop a more severe    form of alloxan-induced diabetes. Am J Physiol Endocrinol Metab.    2000 April; 278(4):E684-91.-   24. Nafissi N, Foldvari M, Neuroprotective therapies in    glaucoma: II. Genetic nanotechnology tools, Front Neurosci. 2015; 9:    355.-   25. Poyner D R. Calcitonin gene-related peptide: multiple actions,    multiple receptors. Pharmacol Ther. 1992; 56(1):23-51.-   26. Poyner D R, Sexton P M, Marshall I, Smith D M, Quirion R, et al.    International Union of Pharmacology. XXXII. The mammalian calcitonin    gene-related peptides, adrenomedullin, amylin, and calcitonin    receptors. Pharmacol. Rev. 2002; 54:233-46-   27. Ragauskas S, Leinonen H, Puranen J, Ronkko S, Nymark S,    Gurevicius K, Lipponen A, Kontkanen O, Puolivali J, Tanila H,    Kalesnykas G (2014). Early retinal function deficit without    prominent morphological changes in the R6/2 mouse model of    Huntington's disease. PLoS One. 3; 9(12):e113317.    doi:10.1371/journal.pone.0113317.-   28. Ragauskas S, Leinonen H, Puranen J, Ronkko S, Nymark S,    Gurevicius K, Lipponen A, Kontkanen O, Puolivali J, Tanila H,    Kalesnykas G (2014). Early retinal function deficit without    prominent morphological changes in the R6/2 mouse model of    Huntington's disease. PLoS One. 3; 9(12):e113317.    doi:10.1371/journal.pone.0113317.-   29. Roh J, Chang C L, Bhalla A, Klein C and Teddy Hsu S Y T.    Intermedin Is a Calcitonin/Calcitonin Gene-related Peptide Family    Peptide Acting through the Calcitonin Receptor-like    Receptor/Receptor Activity-modifying Protein Receptor Complexes. J    Biol Chem. 2004 Feb. 20; 279(8):7264-74. Epub 2003 Nov. 13.-   30. Rovero P1, Guliani S, Maggi C A. CGRP antagonist activity of    short C-terminal fragments of human alpha CGRP, CGRP(23-37) and    CGRP(19-37). Peptides. 1992 September-October; 13(5):1025-7.-   31. Russo A F, CALCITONIN GENE-RELATED PEPTIDE (CGRP): A New Target    for Migraine, Annu Rev Pharmacol Toxicol. 2015; 55: 533-552.    doi:10.1146/annurev-pharmtox-010814-124701-   32. Salmon A M, Damaj I, Sekine S, Picciotto M R, Marubio L,    Changeux J P. Modulation of morphine analgesia in alpha CGRP mutant    mice. Neuroreport. 1999 Mar. 17; 10(4):849-54.-   33. Salmon A M, Damaj M I, Marubio L M, Epping-Jordan M P,    Merlo-Pich E, Changeux J P. Altered neuroadaptation in opiate    dependence and neurogenic inflammatory nociception in alpha    CGRP-deficient mice. Nat Neurosci. 2001 April; 4(4):357-8.-   34. Shindo T, Kurihara Y, Nishimatsu H, Moriyama N, Kakoki M, Wang    Y, Imai Y, Ebihara A, Kuwaki T, Ju K H, Minamino N, Kangawa K,    Ishikawa T, Fukuda M, Akimoto Y, Kawakami H, Imai T, Morita H,    Yazaki Y, Nagai R, Hirata Y, Kurihara H. Vascular abnormalities and    elevated blood pressure in mice lacking adrenomedullin gene. 2001,    Circulation 104:1964-1971.-   35. Song J, Kim J. Degeneration of Dopaminergic Neurons Due to    Metabolic Alterations and Parkinson's Disease. Front Aging Neurosci.    2016 Mar. 30; 8:65.-   36. Tilakaratne N, Christopoulos G, Zumpe E T, Foord S M and Sexton    P M. Amylin Receptor Phenotypes Derived from Human Calcitonin    Receptor/RAMP Coexpression Exhibit Pharmacological Differences    Dependent on Receptor Isoform and Host Cell Environment. J Pharmacol    Exp Ther. 2000 July; 294(1):61-72.-   37. Zhang L, Hoff A O, Wimalawansa S J, Cote G J, Gagel R F,    Westlund K N. Arthritic calcitonin/alpha calcitonin gene-related    peptide knockout mice have reduced nociceptive hypersensitivity.    Pain. 2001 January; 89(2-3):265-73.-   38. Zhang Z, Winborn C S, Marquez de Prado B, and Russo A F (2007).    Sensitization of Calcitonin Gene-Related Peptide Receptors by    Receptor Activity-Modifying Protein-1 in the Trigeminal Ganglion.    The Journal of Neuroscience, 7 Mar. 2007, 27(10): 2693-2703; doi:    10.1523/JNEUROSCI.4542-06.2007

1-13. (canceled)
 14. A method of reducing LDL in a patient in needthereof, the method comprising: administering to the patient aneffective amount of CGRP receptor antagonist or pharmaceuticallyacceptable salt thereof.
 15. The method of claim 14, wherein the CGRPreceptor antagonist is a peptide or pharmaceutically acceptable saltthereof comprising a structure of Formula I:X¹—Y¹—Z¹   (I) wherein: X¹ is a modified N-terminal fragment (i.e.,region) of calcitonin gene-related peptide comprising from five to sevenamino acid residues, wherein only two amino acid residues of theN-terminal fragment are cysteine (Cys), wherein the residue at theC-terminal end of the region is Cys, and wherein the residue immediatelypreceding the C-terminal Cys residue of the region is a non-threoninesubstitution of the threonine (Thr) residue of position 6 of human GCRP;Y¹ is a central core region wherein at least one amino acid of thecentral core is arginine (Arg) or lysine (Lys) and the central corecomprises an α-helix; and Z¹ is a modified C-terminal fragment (i.e.,region) of calcitonin gene-related peptide comprising from five to sevenamino acid residues with a C-terminal amide, where at least one aminoacid of the C-terminal fragment is phenylalanine (Phe), tyrosine (Tyr),proline (Pro) or hydroxyproline (Hyp).
 16. The method of claim 14,wherein the CGRP receptor antagonist comprises a sequence set forth inone of SEQ ID NO: 1(NH₂-Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 2(NH2-Ala-Cys-Asp-Thr-Ala-Ser-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 3(NH2-Ala-Cys-Asp-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH₂),SEQ ID NO: 4(NH2-Ala-Cys-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 5(NH2-Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 6(NH2-Ala-Cys-Arg-Phe-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 7(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 8(NH2-Cys-Ser-Asn-Thr-Ala-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 9(NH₂-Ala-Cys-Asp-Thr-Ala-Leu-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 10(NH2-Ala-Cys-Asp-Thr-Ala-Ile-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 11(NH2-Ala-Cys-Asn-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 12(NH2-Cys-Ser-Asn-Thr-Ala-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH₂),SEQ ID NO: 13(NH2-Ala-Cys-Asn-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro-NH2),SEQ ID NO: 14(Ala-Cys-Val-Leu-Gly-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Val-Asp-Pro-Ser-Ser-Pro-His-Ser-Tyr-NH2),SEQ ID NO: 15(Ala-Cys-Asp-Thr-Ala-Ala-Cys-Val-Thr-His-Arg-Leu-Ala-Gly-Leu-Leu-Ser-Arg-Ser-Gly-Gly-Val-Val-Lys-Asn-Asn-Phe-Val-Pro-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2),SEQ ID NO: 57(NH2-Ala-Cys-Asp-Leu-Ser-Ala-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or SEQ ID NO: 58(NH2-Ala-Cys-Asp-Leu-Ser-Val-Cys-Val-Leu-Gly-Arg-Leu-Ser-Gln-Glu-Leu-His-Arg-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly-Ser-Lys-Ala-Phe-NH2)or a pharmaceutically acceptable salt thereof.
 17. The method of claim14, wherein the CGRP antagonist comprises a sequence selected from thegroup consisting of the sequences set forth in SEQ ID NO: 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12 and
 13. 18. The method of claim 14, wherein thepatient is suffering from high LDL concentration in the blood.
 19. Themethod of claim 14, further comprising monitoring or measuring the levelor amount of LDL in said patient before, during, or after administrationof the effective amount of CGRP receptor antagonist.
 20. The method ofclaim 14, wherein the patient is a male.
 21. The method of claim 14,wherein the patient has familial hypercholesterolemia.
 22. The method ofclaim 14, wherein the CGRP receptor antagonist is administered dermally,intradermally, subcutaneously, via dermal infusion, via subcutaneousinfusion, intravenously, buccally, intramuscularly, sublingually ororally.
 23. The method of claim 14, wherein the effective amountcomprises an amount of about 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg,200 μg, 300 μg, 400 μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg, 1 mg, 10mg, 20 mg, 30 mg, 40 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg,600 mg, 700 mg, 800 mg, 900 mg or 1000 mg or any amount in between arange defined by any two aforementioned values.
 24. The method of claim14, wherein the administering is performed at least four times a day,three times a day, two times a day, or once a day.